WO2022106630A1 - Formulations stables comprenant de la pipéracilline et/ou du tazobactam - Google Patents
Formulations stables comprenant de la pipéracilline et/ou du tazobactam Download PDFInfo
- Publication number
- WO2022106630A1 WO2022106630A1 PCT/EP2021/082324 EP2021082324W WO2022106630A1 WO 2022106630 A1 WO2022106630 A1 WO 2022106630A1 EP 2021082324 W EP2021082324 W EP 2021082324W WO 2022106630 A1 WO2022106630 A1 WO 2022106630A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acetyl
- amino acid
- alaninamide
- piperacillin
- tazobactam
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 248
- 229960002292 piperacillin Drugs 0.000 title claims abstract description 112
- 229960003865 tazobactam Drugs 0.000 title claims abstract description 108
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 title claims abstract description 108
- 238000009472 formulation Methods 0.000 title claims description 128
- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 title abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 348
- -1 N-acetyl amino acid amide Chemical class 0.000 claims abstract description 199
- CXURPNUIYCJENH-LURJTMIESA-N (2s)-1-acetylpyrrolidine-2-carboxamide Chemical compound CC(=O)N1CCC[C@H]1C(N)=O CXURPNUIYCJENH-LURJTMIESA-N 0.000 claims description 199
- 235000001014 amino acid Nutrition 0.000 claims description 190
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 claims description 190
- 239000002904 solvent Substances 0.000 claims description 115
- DVOVBGJJSFSOPZ-VKHMYHEASA-N (2s)-2-acetamidopropanamide Chemical compound NC(=O)[C@H](C)NC(C)=O DVOVBGJJSFSOPZ-VKHMYHEASA-N 0.000 claims description 106
- 230000005496 eutectics Effects 0.000 claims description 105
- JYSQHZCNOOQLII-GSVOUGTGSA-N (2R)-N-acetyl-2-aminopropanamide Chemical compound C[C@@H](N)C(=O)NC(C)=O JYSQHZCNOOQLII-GSVOUGTGSA-N 0.000 claims description 97
- 150000001875 compounds Chemical class 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 21
- 150000001413 amino acids Chemical class 0.000 claims description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 150000001408 amides Chemical class 0.000 claims description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
- 125000003047 N-acetyl group Chemical group 0.000 claims description 6
- JYSQHZCNOOQLII-VKHMYHEASA-N (2s)-n-acetyl-2-aminopropanamide Chemical compound C[C@H](N)C(=O)NC(C)=O JYSQHZCNOOQLII-VKHMYHEASA-N 0.000 claims description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 235000005985 organic acids Nutrition 0.000 claims description 4
- 235000000346 sugar Nutrition 0.000 claims description 4
- 150000008163 sugars Chemical class 0.000 claims description 4
- HNGIZKAMDMBRKJ-LBPRGKRZSA-N (2S)-2-acetamido-3-(1H-indol-3-yl)propanamide Chemical compound C1=CC=C2C(C[C@H](NC(=O)C)C(N)=O)=CNC2=C1 HNGIZKAMDMBRKJ-LBPRGKRZSA-N 0.000 claims description 3
- FOOYOLJJLOKDPB-BYPYZUCNSA-N (2S)-N-acetyl-2-amino-3-hydroxypropanamide Chemical compound CC(=O)NC(=O)[C@@H](N)CO FOOYOLJJLOKDPB-BYPYZUCNSA-N 0.000 claims description 3
- QUYFAKDSSWJPJQ-YFKPBYRVSA-N (2S)-N-acetyl-2-aminopentanediamide Chemical compound CC(=O)NC(=O)[C@@H](N)CCC(N)=O QUYFAKDSSWJPJQ-YFKPBYRVSA-N 0.000 claims description 3
- UECDWMGGNAYEKF-JTQLQIEISA-N (2s)-n-acetyl-2-amino-3-(4-hydroxyphenyl)propanamide Chemical compound CC(=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 UECDWMGGNAYEKF-JTQLQIEISA-N 0.000 claims description 3
- NUPDDTQMGFCFGB-JTQLQIEISA-N (2s)-n-acetyl-2-amino-3-phenylpropanamide Chemical compound CC(=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 NUPDDTQMGFCFGB-JTQLQIEISA-N 0.000 claims description 3
- OIRDKWJJMSJIEY-LURJTMIESA-N (2s)-n-acetyl-2-amino-4-methylsulfanylbutanamide Chemical compound CSCC[C@H](N)C(=O)NC(C)=O OIRDKWJJMSJIEY-LURJTMIESA-N 0.000 claims description 3
- WQELDIQOHGAHEM-UHFFFAOYSA-N 2-acetamidoacetamide Chemical compound CC(=O)NCC(N)=O WQELDIQOHGAHEM-UHFFFAOYSA-N 0.000 claims description 3
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 claims description 3
- AXMXADRFXMQRCN-YFKPBYRVSA-N C(C)(=O)NC([C@@H](N)CCC(=O)O)=O Chemical compound C(C)(=O)NC([C@@H](N)CCC(=O)O)=O AXMXADRFXMQRCN-YFKPBYRVSA-N 0.000 claims description 3
- 235000019743 Choline chloride Nutrition 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- OTCCIMWXFLJLIA-UHFFFAOYSA-N N-acetyl-DL-aspartic acid Natural products CC(=O)NC(C(O)=O)CC(O)=O OTCCIMWXFLJLIA-UHFFFAOYSA-N 0.000 claims description 3
- OTCCIMWXFLJLIA-BYPYZUCNSA-N N-acetyl-L-aspartic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(O)=O OTCCIMWXFLJLIA-BYPYZUCNSA-N 0.000 claims description 3
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 claims description 3
- 229960003178 choline chloride Drugs 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 229920000642 polymer Polymers 0.000 claims description 3
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 3
- 150000004023 quaternary phosphonium compounds Chemical class 0.000 claims description 3
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 3
- 229940081974 saccharin Drugs 0.000 claims description 3
- 235000019204 saccharin Nutrition 0.000 claims description 3
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- UJCHIZDEQZMODR-SCSAIBSYSA-N acetylcysteinamide Chemical compound CC(=O)N[C@H](CS)C(N)=O UJCHIZDEQZMODR-SCSAIBSYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 28
- 238000002156 mixing Methods 0.000 abstract description 12
- 230000000087 stabilizing effect Effects 0.000 abstract description 3
- 208000035143 Bacterial infection Diseases 0.000 abstract 1
- 208000022362 bacterial infectious disease Diseases 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 155
- 229960000373 tazobactam sodium Drugs 0.000 description 86
- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical compound COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 description 84
- 229960005264 piperacillin sodium Drugs 0.000 description 84
- 239000008186 active pharmaceutical agent Substances 0.000 description 41
- 239000000243 solution Substances 0.000 description 34
- 239000000872 buffer Substances 0.000 description 32
- 239000012535 impurity Substances 0.000 description 32
- 239000007788 liquid Substances 0.000 description 32
- 239000006172 buffering agent Substances 0.000 description 30
- 239000002738 chelating agent Substances 0.000 description 24
- TUPFOYXHAYOHIB-YCAIQWGJSA-M sodium;(2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]h Chemical compound [Na+].C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 TUPFOYXHAYOHIB-YCAIQWGJSA-M 0.000 description 24
- 230000003139 buffering effect Effects 0.000 description 20
- QZTKDVCDBIDYMD-UHFFFAOYSA-N 2,2'-[(2-amino-2-oxoethyl)imino]diacetic acid Chemical compound NC(=O)CN(CC(O)=O)CC(O)=O QZTKDVCDBIDYMD-UHFFFAOYSA-N 0.000 description 17
- 102000006635 beta-lactamase Human genes 0.000 description 14
- 230000008569 process Effects 0.000 description 14
- 108090000204 Dipeptidase 1 Proteins 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 8
- 230000015556 catabolic process Effects 0.000 description 8
- 238000006731 degradation reaction Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 241000191967 Staphylococcus aureus Species 0.000 description 7
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 7
- 239000002132 β-lactam antibiotic Substances 0.000 description 7
- 229940124586 β-lactam antibiotics Drugs 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003781 beta lactamase inhibitor Substances 0.000 description 6
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 5
- 239000007979 citrate buffer Substances 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- 239000012905 visible particle Substances 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- 229940126062 Compound A Drugs 0.000 description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 206010035664 Pneumonia Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000003385 bacteriostatic effect Effects 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 239000012669 liquid formulation Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 4
- LITBAYYWXZOHAW-XDZRHBBOSA-N (2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]hept Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 LITBAYYWXZOHAW-XDZRHBBOSA-N 0.000 description 3
- AJTVSSFTXWNIRG-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]ethanesulfonic acid Chemical compound OCC[NH+](CCO)CCS([O-])(=O)=O AJTVSSFTXWNIRG-UHFFFAOYSA-N 0.000 description 3
- XCBLFURAFHFFJF-UHFFFAOYSA-N 3-[bis(2-hydroxyethyl)azaniumyl]-2-hydroxypropane-1-sulfonate Chemical compound OCCN(CCO)CC(O)CS(O)(=O)=O XCBLFURAFHFFJF-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108020004256 Beta-lactamase Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 208000008745 Healthcare-Associated Pneumonia Diseases 0.000 description 3
- 241001508691 Martes zibellina Species 0.000 description 3
- DBXNUXBLKRLWFA-UHFFFAOYSA-N N-(2-acetamido)-2-aminoethanesulfonic acid Chemical compound NC(=O)CNCCS(O)(=O)=O DBXNUXBLKRLWFA-UHFFFAOYSA-N 0.000 description 3
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 3
- 125000003460 beta-lactamyl group Chemical group 0.000 description 3
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 230000000813 microbial effect Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 229940100688 oral solution Drugs 0.000 description 3
- 229940100692 oral suspension Drugs 0.000 description 3
- 239000006174 pH buffer Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 238000010257 thawing Methods 0.000 description 3
- UJCHIZDEQZMODR-BYPYZUCNSA-N (2r)-2-acetamido-3-sulfanylpropanamide Chemical compound CC(=O)N[C@@H](CS)C(N)=O UJCHIZDEQZMODR-BYPYZUCNSA-N 0.000 description 2
- OKSUEATVFIVTFV-WBTNSWJXSA-N (2r,4s)-2-[(r)-carboxy-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid Chemical class O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@H](C(O)=O)[C@H]1SC(C)(C)[C@H](C(O)=O)N1 OKSUEATVFIVTFV-WBTNSWJXSA-N 0.000 description 2
- VOYSKJXXUJMOBQ-ZETCQYMHSA-N (2s)-n-acetyl-2,6-diaminohexanamide Chemical compound CC(=O)NC(=O)[C@@H](N)CCCCN VOYSKJXXUJMOBQ-ZETCQYMHSA-N 0.000 description 2
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- ACERFIHBIWMFOR-UHFFFAOYSA-N 2-hydroxy-3-[(1-hydroxy-2-methylpropan-2-yl)azaniumyl]propane-1-sulfonate Chemical compound OCC(C)(C)NCC(O)CS(O)(=O)=O ACERFIHBIWMFOR-UHFFFAOYSA-N 0.000 description 2
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 2
- NUFBIAUZAMHTSP-UHFFFAOYSA-N 3-(n-morpholino)-2-hydroxypropanesulfonic acid Chemical compound OS(=O)(=O)CC(O)CN1CCOCC1 NUFBIAUZAMHTSP-UHFFFAOYSA-N 0.000 description 2
- RZQXOGQSPBYUKH-UHFFFAOYSA-N 3-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]azaniumyl]-2-hydroxypropane-1-sulfonate Chemical compound OCC(CO)(CO)NCC(O)CS(O)(=O)=O RZQXOGQSPBYUKH-UHFFFAOYSA-N 0.000 description 2
- LOJNFONOHINEFI-UHFFFAOYSA-N 4-[4-(2-hydroxyethyl)piperazin-1-yl]butane-1-sulfonic acid Chemical compound OCCN1CCN(CCCCS(O)(=O)=O)CC1 LOJNFONOHINEFI-UHFFFAOYSA-N 0.000 description 2
- 239000007991 ACES buffer Substances 0.000 description 2
- 108700016232 Arg(2)-Sar(4)- dermorphin (1-4) Proteins 0.000 description 2
- 239000007989 BIS-Tris Propane buffer Substances 0.000 description 2
- 241000606124 Bacteroides fragilis Species 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- OWXMKDGYPWMGEB-UHFFFAOYSA-N HEPPS Chemical compound OCCN1CCN(CCCS(O)(=O)=O)CC1 OWXMKDGYPWMGEB-UHFFFAOYSA-N 0.000 description 2
- GIZQLVPDAOBAFN-UHFFFAOYSA-N HEPPSO Chemical compound OCCN1CCN(CC(O)CS(O)(=O)=O)CC1 GIZQLVPDAOBAFN-UHFFFAOYSA-N 0.000 description 2
- 241000606768 Haemophilus influenzae Species 0.000 description 2
- 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 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- FSVCELGFZIQNCK-UHFFFAOYSA-N N,N-bis(2-hydroxyethyl)glycine Chemical compound OCCN(CCO)CC(O)=O FSVCELGFZIQNCK-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 description 2
- 239000007997 Tricine buffer Substances 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 206010000269 abscess Diseases 0.000 description 2
- 241001148470 aerobic bacillus Species 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000007998 bicine buffer Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- HHKZCCWKTZRCCL-UHFFFAOYSA-N bis-tris propane Chemical compound OCC(CO)(CO)NCCCNC(CO)(CO)CO HHKZCCWKTZRCCL-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 description 2
- 244000000059 gram-positive pathogen Species 0.000 description 2
- 229940047650 haemophilus influenzae Drugs 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229940104641 piperacillin / tazobactam Drugs 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 206010040872 skin infection Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000008227 sterile water for injection Substances 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- JDRRFRJXPYVECF-UHFFFAOYSA-N 1-morpholin-4-ylbutane-1-sulfonic acid Chemical compound CCCC(S(O)(=O)=O)N1CCOCC1 JDRRFRJXPYVECF-UHFFFAOYSA-N 0.000 description 1
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 1
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 1
- VKZRWSNIWNFCIQ-UHFFFAOYSA-N 2-[2-(1,2-dicarboxyethylamino)ethylamino]butanedioic acid Chemical compound OC(=O)CC(C(O)=O)NCCNC(C(O)=O)CC(O)=O VKZRWSNIWNFCIQ-UHFFFAOYSA-N 0.000 description 1
- JHALWMSZGCVVEM-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CC1 JHALWMSZGCVVEM-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- UMLWEPGSWQNXQX-UHFFFAOYSA-N 2-diethoxyphosphorylpropanenitrile Chemical compound CCOP(=O)(OCC)C(C)C#N UMLWEPGSWQNXQX-UHFFFAOYSA-N 0.000 description 1
- LVQFQZZGTZFUNF-UHFFFAOYSA-N 2-hydroxy-3-[4-(2-hydroxy-3-sulfonatopropyl)piperazine-1,4-diium-1-yl]propane-1-sulfonate Chemical compound OS(=O)(=O)CC(O)CN1CCN(CC(O)CS(O)(=O)=O)CC1 LVQFQZZGTZFUNF-UHFFFAOYSA-N 0.000 description 1
- HSXUNHYXJWDLDK-UHFFFAOYSA-N 2-hydroxypropane-1-sulfonic acid Chemical compound CC(O)CS(O)(=O)=O HSXUNHYXJWDLDK-UHFFFAOYSA-N 0.000 description 1
- YPJHXRAHMUKXAE-UHFFFAOYSA-N 3-diethoxyphosphorylprop-1-ene Chemical compound CCOP(=O)(CC=C)OCC YPJHXRAHMUKXAE-UHFFFAOYSA-N 0.000 description 1
- VTOWJTPBPWTSMK-UHFFFAOYSA-N 4-morpholin-4-ylbutane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCCN1CCOCC1 VTOWJTPBPWTSMK-UHFFFAOYSA-N 0.000 description 1
- 241000588626 Acinetobacter baumannii Species 0.000 description 1
- 206010003011 Appendicitis Diseases 0.000 description 1
- 241001135228 Bacteroides ovatus Species 0.000 description 1
- 241000606123 Bacteroides thetaiotaomicron Species 0.000 description 1
- 241000606215 Bacteroides vulgatus Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010060803 Diabetic foot infection Diseases 0.000 description 1
- 208000004145 Endometritis Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108010008488 Glycylglycine Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 239000007996 HEPPS buffer Substances 0.000 description 1
- 208000036209 Intraabdominal Infections Diseases 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- JYXGIOKAKDAARW-UHFFFAOYSA-N N-(2-hydroxyethyl)iminodiacetic acid Chemical compound OCCN(CC(O)=O)CC(O)=O JYXGIOKAKDAARW-UHFFFAOYSA-N 0.000 description 1
- YNLCVAQJIKOXER-UHFFFAOYSA-N N-[tris(hydroxymethyl)methyl]-3-aminopropanesulfonic acid Chemical compound OCC(CO)(CO)NCCCS(O)(=O)=O YNLCVAQJIKOXER-UHFFFAOYSA-N 0.000 description 1
- VFTZCDVTMZWNBF-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-4-aminobutanesulfonic acid Chemical compound OCC(CO)(CO)NCCCCS(O)(=O)=O VFTZCDVTMZWNBF-UHFFFAOYSA-N 0.000 description 1
- 239000007990 PIPES buffer Substances 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 206010058674 Pelvic Infection Diseases 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 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 description 1
- 206010034576 Peripheral ischaemia Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 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
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N Trimethylene glycol Natural products OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 208000034953 Twin anemia-polycythemia sequence Diseases 0.000 description 1
- YDONNITUKPKTIG-UHFFFAOYSA-N [Nitrilotris(methylene)]trisphosphonic acid Chemical compound OP(O)(=O)CN(CP(O)(O)=O)CP(O)(O)=O YDONNITUKPKTIG-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000244 anti-pseudomonal effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008228 bacteriostatic water for injection Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000004067 bulking agent Substances 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
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229940090960 diethylenetriamine pentamethylene phosphonic acid Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- DUYCTCQXNHFCSJ-UHFFFAOYSA-N dtpmp Chemical compound OP(=O)(O)CN(CP(O)(O)=O)CCN(CP(O)(=O)O)CCN(CP(O)(O)=O)CP(O)(O)=O DUYCTCQXNHFCSJ-UHFFFAOYSA-N 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 229940043257 glycylglycine Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- NBZBKCUXIYYUSX-UHFFFAOYSA-N iminodiacetic acid Chemical compound OC(=O)CNCC(O)=O NBZBKCUXIYYUSX-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229940049920 malate Drugs 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000008063 pharmaceutical solvent Substances 0.000 description 1
- SJWPTBFNZAZFSH-UHFFFAOYSA-N pmpp Chemical compound C1CCSC2=NC=NC3=C2N=CN3CCCN2C(=O)N(C)C(=O)C1=C2 SJWPTBFNZAZFSH-UHFFFAOYSA-N 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000012898 sample dilution Substances 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- VBJGJHBYWREJQD-UHFFFAOYSA-M sodium;dihydrogen phosphate;dihydrate Chemical compound O.O.[Na+].OP(O)([O-])=O VBJGJHBYWREJQD-UHFFFAOYSA-M 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical class O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 239000012904 visual particle Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
Definitions
- the present invention relates to pharmaceutical compositions comprising piperacillin and/or tazobactam and at least one N-acetyl amino acid amide. Such compositions provide good stability over time.
- Piperacillin is a semisynthetic broad-spectrum P-lactam antibiotic, which is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria.
- Piperacillin ( Figure 1) comprises a polar side chain that enhances penetration into gram-negative bacteria and reduces susceptibility to cleavage by gram-negative beta-lactamase enzymes. These properties confer activity against the important hospital pathogen Pseudomonas aeruginosa. Thus, piperacillin is sometimes referred to as an "anti-pseudomonal penicillin”.
- FIG. 1 Molecular structure of piperacillin [004] When used alone, piperacillin lacks strong activity against the gram-positive pathogens such as Staphylococcus aureus, as the beta-lactam ring is hydrolyzed by the bacteria's beta-lactamase.
- Beta-lactamases are family of enzymes involved in bacterial resistance to betalactam antibiotics. They act by breaking the beta-lactam ring that allows penicillin- like antibiotics to work. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although ⁇ -lactamase inhibitors have little antibiotic activity of their own, they prevent degradation of beta-lactam antibiotics by beta-lactamases secreted by resistant microorganisms and thus restore activity of the partner beta-lactam antibiotics.
- Piperacillin is most commonly used in combination with the beta-lactamase inhibitor tazobactam (Formula 2).
- Tazobactam is a penicillanic acid sulfone derivative and beta-lactamase inhibitor with antibacterial activity.
- Tazobactam contains a beta-lactam ring and irreversibly binds to beta-lactamase at or near its active site. This protects other beta-lactam antibiotics from beta-lactamase catalysis. This drug is used in conjunction with betalactamase susceptible penicillins, such as piperacillin, to treat infections caused by beta-lactamase producing organisms.
- Piperacillin-tazobactam is recommended as part of a three drug regimen for the treatment of hospital-acquired pneumonia suspected as being due to infection by multi-drug resistant pathogens. It is also one of several antibacterials recommended for the treatment of infections known to be caused by anaerobic gram-negative rods.
- piperacillin and/or tazobactam are commonly commercially available in a form of lyophilized powder for intravenous infusion which requires reconstitution and subsequent dilution step prior to patient administration.
- compositions of piperacillin and/or tazobactam suitable for administration to a subject and which possess long term storage stability both in respect of degradation of active pharmaceutical ingredients and in respect of the formation of individual impurities.
- composition comprising at least piperacillin and/or tazobactam, its pharmaceutical salts or derivative thereof and at least one N- acetyl amino acid amide. It has been found that the pharmaceutical formulation described herein possess surprisingly enhanced storage stability.
- pharmaceutical formulation of the present disclosure is in liquid form.
- piperacillin and/or tazobactam are formulated in formulations according to the present disclosure, degradation product formation is retarded, and accordingly, such formulations exhibit prolonged chemical stability and provide more flexible storage conditions and handling when stored under refrigerated conditions, i.e. at a temperature of from 2°C to 8°C.
- the pharmaceutical formulation in accordance with the present disclosure has improved stability under room temperature conditions.
- a liquid formulation according to the present disclosure is stable at a temperature of from 2°C to 8°C for a certain period of time.
- a liquid formulation according to the present disclosure is stable under room temperature conditions for a certain period of time.
- Disclosed formulations may enhance activity and/or efficacy of piperacillin and/or tazobactam.
- compositions according to the present disclosure may be used to treat a patient with a microbial infection by administering the pharmaceutical formulation.
- Liquid formulation of the pharmaceutical formulation in accordance to this disclosure may be optionally diluted before administration.
- compositions comprising at least piperacillin and/or tazobactam, its pharmaceutical salt or derivative thereof and at least one N- acetyl amino acid amide.
- N-Acetyl amino acid amide is an amino acid derivative where a-nitrogen of amino acid is N-acetylated and where, instead of carboxylic acid group, amide group is bound to the a carbon atom of the amino acid group.
- a N-acetylated amino acid amide please see Figure 3 below, showing the structure of N-acetyl alaninamide:
- At least one N-acetyl amino acid amide is also named a “first N-acetyl amino acid amide”.
- pharmaceutical formulation comprises at least two N-acetyl amino acid amides.
- N-acetyl amino acid amides are also named a “first N-acetyl amino acid amide” and a “second N-acetyl amino acid amide”.
- Formulations according to the present disclosure showed surprising stability for a reasonable period of time, when stored at a temperature of from 2°C to 8°C, such as, e.g., at a temperature of 2°C , 3°C or less, 4°C or less, 5°C or less, 6°C or less, 7°C or less or 8°C or less.
- room temperature is a room temperature which is from 20 °C to 25 °C.
- Term “stable” as used herein refers to a pharmaceutical formulation containing active pharmaceutical ingredient having sufficient utility as a pharmaceutical product, i.e. that the pharmaceutical formulation exhibits an acceptable purity of the active pharmaceutical ingredient or an acceptable purity decrease of the active pharmaceutical ingredient after a certain period of time.
- active pharmaceutical ingredient as used herein is meant active pharmaceutical ingredient selected from piperacillin and tazobactam. Accordingly, in a stable solution or formulation unacceptable amount of degradation of the active pharmaceutical ingredient is avoided. Further, in a stable formulation, pharmaceutically desirable appearance such as no visible particles (for example, no visible particles to the naked eye) is retained. Visual inspection may be performed as follows: the vial under inspection is gently swirled and inverted, ensuring that no air bubbles are produced, and inspected for approximately 5 sec with naked eye.
- the stability can be determined by measuring of the active pharmaceutical ingredient remaining in the solution or composition according to the invention after a predetermined time period, preferably expressed as a percentage, for example as a peak-area percentage of a chromatogram (purity). If the formulation initially contains the active pharmaceutical ingredient in a certain purity, the stability of the formulation will be reflected by a decrease/drop in the chromatographic purity of the active pharmaceutical ingredient formulation over time, where a stable formulation would contain the active pharmaceutical ingredient in a specified chromatographic purity after predetermined time period.
- Stability of the formulation may also be expressed in terms of concentration or absolute amount of the active pharmaceutical ingredient.
- Stability may be defined by the amount of the active pharmaceutical ingredient in the formulation after a certain period of time.
- Stability may also be defined by the amount of total or individual impurities in the formulation after a certain period of time. Stability may also be defined by increase of total or individual impurities generated after a suitable period of time.
- the stability can be determined by measuring the amount of each individual impurity in the formulation according to the invention after a predetermined time period, preferably expressed as a percentage, for example as a peak-area percentage of a chromatogram.
- impurity as used herein is meant a degradation impurity of the active pharmaceutical ingredient in the pharmaceutical formulation.
- impurity By the individual impurities related to tazobactam, it is predominantly meant
- Tazobactam related compound A Structure of Tazobactam related compound A is shown below as Figure 4.
- Piperacillin degrades into the following main degradation impurities: Piperacillin penicilloic acid isomer 1 and 2, Piperacillin penilloic acids, Piperacillin dimer and Piperazinedione-carbonyl D-phenylglycyl -glycine.
- Impurities being present in the formulation may be expressed as a percentage, for example as a peak-area percentage of a HPLC chromatogram.
- Disclosed formulations also minimize degradation of active pharmaceutical ingredient to impurities.
- Disclosed formulations retain pharmaceutically desirable appearance such as no visible particles.
- stable is defined as no more than 10% of purity decrease/drop of individual active pharmaceutical ingredient in the pharmaceutical formulation, determined by HPLC analysis.
- a stable composition can be one which has not more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, of purity decrease/drop for individual active pharmaceutical ingredient after a predetermined time period.
- a stable composition can be one which has not more than 8% of purity decrease/drop for individual active pharmaceutical ingredient after a predetermined time period.
- stable is defined as no more than 5% increase (expressed by peak-area percentage) of each individual impurity formation after a predetermined time period.
- a stable composition can be one that has not more than 1%, 2%, 3%, 4%, 5%, increase (expressed by peak-area percentage) of individual impurity formation after a predetermined time period.
- the pharmaceutical composition according to the present disclosure is stable over time periods of 7 days (1 week), 14 days (2 weeks), 30 days (1 month), 60 days (2 months), 3 months, 4 months, 180 days (6 months), 9 months, 12 months (1 year), 14 months, 16 months, 18 months, 20 months, 24 months and longer at temperatures of 2-8°C.
- the pharmaceutical composition described herein is stable over time periods of 7 days (1 week), 14 days (2 weeks), 22 days, 30 days (1 month), 60 days (2 months), 3 months, 6 months and longer at room temperature.
- compositions described herein are stable for at least 4 days at temperature of 30°C.
- compositions described herein are stable for at least 11 days at temperature of 30°C.
- a stable or stabilized composition can be one that has not more than 5% increase of individual impurity formation over 6 months and longer at temperatures of 2-8°C.
- a stable or stabilized composition can be one that has not more than 5% increase of individual impurity formation after 12 months and longer at temperatures of 2-8°C.
- a stable or stabilized composition of tazobactam can be one that has not more than 4% increase of Tazobactam related compound A after 6 months and longer at temperatures of 2-8°C.
- a stable or stabilized composition can be one wherein purity of active pharmaceutical ingredient after certain period of time is not less than 90%.
- a sable or stabilized composition can be one wherein the purity of active pharmaceutical ingredient after 2 months at 2-8 °C is not less than 92%.
- a sable or stabilized composition can be one wherein the purity of active pharmaceutical ingredient present after 4 months at 2-8 °C is not less than 92%. [059] In an aspect, a sable or stabilized composition can be one wherein the purity of active pharmaceutical ingredient present after 12 months at 2-8 °C is not less than 92%.
- the pharmaceutical composition according to this disclosure is stable at least 14 days at 25°C.
- the pharmaceutical composition according this disclosure is stable at least 22 days at 25 °C.
- the pharmaceutical composition comprising tazobactam is stable for at least 60 days at 25 °C, as demonstrated by determining the amount of Tazobactam A present in the pharmaceutical composition at 60 days, and wherein the amount of the Tazobactam A present is not more than 10%.
- composition or “pharmaceutically acceptable composition” as used herein, is meant any composition suitable and intended for in vivo use, for example administration to a patient or a subject.
- patient and “subject” are interchangeable and refer to any human or animal individual who is receiving a composition as described herein.
- composition As used herein, the terms “pharmaceutical composition”, “pharmaceutically acceptable composition”, “pharmaceutical formulation”, “composition” and “formulation” are used interchangeably.
- piperacillin and/or tazobactam is in form of a salt.
- Piperacillin and/or tazobactam salt can be selected from calcium, sodium, magnesium or potassium salt.
- piperacillin and/or tazobactam is in form of sodium salt.
- pharmaceutical formulation comprises at least piperacillin, its salt and derivative thereof.
- pharmaceutical formulation comprises at least tazobactam, its salt and derivative thereof.
- pharmaceutical formulation comprises at least piperacillin sodium.
- pharmaceutical formulation comprises at least tazobactam sodium.
- pharmaceutical formulation comprises at least piperacillin and at least one beta-lactamase inhibitor.
- pharmaceutical formulation comprises at least one beta-lactam antibiotic and tazobactam.
- pharmaceutical formulation comprises piperacillin and tazobactam, its salt and derivative thereof.
- weight ratio of piperacillin to tazobactam can be from 4: 1 to 8: 1. In an aspect, the weight ratio of piperacillin to tazobactam is 8: 1.
- pharmaceutical formulation is liquid.
- pharmaceutical formulation may be oral suspension or solution.
- pharmaceutical formulation comprises water.
- pharmaceutical formulation may comprise less than 99% w/V of water.
- pharmaceutical formulation may comprise less than 60% w/V of water.
- pharmaceutical formulation comprises less than 50% w/V of water.
- pharmaceutical formulation comprises less than 45% w/V, 40% w/V, 35% w/V, 30% w /V, 25% w /V, 20% w /V, 15% w /V, 10% w /V, 8% w /V, 6% w /V, 4% w /V, 2% w /V, 1% w /V of water.
- pharmaceutical formulation is semisolid, like ointments, creams, gels, or pastes.
- the semisolid composition is gel.
- an N-acetyl amino acid amide may be N- acetyl cysteine amide, N-acetyl glutaminamide, N-acetyl aspartic acid amide, N- acetyl glycinamide, N-acetyl alaninamide, N-acetyl prolinamide, N-acetyl serinamide, N-acetyl threoninamide, N-acetyl valinamide, N-acetyl isoleucinamide, N-Acetyl leucinamide, N-acetyl methioninamide, N-acetyl phenylalaninamide, N- acetyl tyrosinamide, N-acetyl asparaginamide, N-acetyl glutamic acid amide, N- acetyl histidinamide, N-acetyl argininamide, N-acetyl citrul
- pharmaceutical formulation comprises at least N-Acetyl alaninamide.
- N-acetyl amino acid amide may be in L configuration, while in some other aspect it may be in D configuration.
- L configuration and D configuration are referred to stereochemistry of amide group consisting of N- acetylated a-nitrogen in N-Acetyl amino acid amide. If this group in Fisher projection formula is turned right, it is a N-acetyl D-amino acid amide. If it is turned left it is a N-acetyl L-amino acid amide.
- pharmaceutical formulation comprises at least N-Acetyl-L- alaninamide (hereinafter NALAA).
- pharmaceutical formulation comprises at least N-acetyl-D- alaninamide (hereinafter NAD AA).
- pharmaceutical formulation comprises at least N-Acetyl-L- prolinamide (hereinafter NALP A).
- a concentration of an N-acetyl amino acid amide is from 1 mg/ml to 1500 mg/ml.
- a concentration of an N-acetyl amino acid amide is from 20 mg/ml to 1000 mg/ml.
- a concentration of an N-acetyl amino acid amide is 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 150 mg/ml, 200 mg/ml, 250 mg/ml, 300 mg/ml, 400 mg/ml, 500 mg/ml, 600 mg/ml, 700 mg/ml, 750mg/ml, 800 mg/ml, 900 mg/ml or 1000 mg/ml.
- a concentration of an N-acetyl amino acid amide is from 300 mg/ml to 750 mg/ml.
- pharmaceutical formulation comprises two N-acetyl amino acid amides.
- pharmaceutical formulation comprises N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
- pharmaceutical formulation comprises N-acetyl-L-prolinamide and N-acetyl-D-alaninamide.
- the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio from 0.2: 1 to 5 : 1.
- the N-acetyl amino acid amide first and the second N-acetyl amino acid amide are in molar ratio of 0.2: 1, 0.3: 1, 0.4: 1, 0.5: 1, of 1 : 1, of 1.5: 1, of 2: 1, of 2.5: 1, of 3: 1, of 4: 1, of 5: 1.
- the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio of 1 : 1.
- pharmaceutical formulation comprises two N-acetyl amino acid amides and a concentration of each N-acetyl amino acid amide is 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 150 mg/ml, 200 mg/ml, 250 mg/ml, 300 mg/ml, 400 mg/ml, 500 mg/ml, 600 mg/ml, 700 mg/ml, 800 mg/ml.
- pharmaceutical formulation comprises two N-acetyl amino acid amides and a concentration of an N-acetyl amino acid amide is 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 150 mg/ml, 200 mg/ml, 250 mg/ml, 300 mg/ml, 400 mg/ml, 500 mg/ml, 600 mg/ml, 700 mg/ml, 750mg/ml, 800 mg/ml.
- pharmaceutical formulation comprises two N-acetyl amino acid amides and a concentration of each N-acetyl amino acid amide is from 300 mg/ml to 600 mg/ml.
- pharmaceutical formulation comprises two N-acetyl amino acid amides and a concentration of each N-acetyl amino acid amide is from 300 to 400 mg/ml.
- pharmaceutical formulation may comprise at least one additional compound selected from nicotinamide, acetamide, benzamide, amino acids, quaternary ammonium compounds, quaternary phosphonium compounds, organic acids, sugars, urea and derivatives thereof, metal salts, choline chloride, sorbitol, ethyl eneglyl col amide, polymers such as PEG, PPG, phenol, glycerol, saccharin, imidazole, its salts or derivatives thereof.
- additional compound selected from nicotinamide, acetamide, benzamide, amino acids, quaternary ammonium compounds, quaternary phosphonium compounds, organic acids, sugars, urea and derivatives thereof, metal salts, choline chloride, sorbitol, ethyl eneglyl col amide, polymers such as PEG, PPG, phenol, glycerol, saccharin, imidazole, its salts or derivatives thereof
- At least one N-acetyl amino acid amide and at least one additional compound are in molar ratio from 0.3: 1 to 3 : 1.
- at least one N-acetyl amino acid amide and at least one additional compound are in molar ratio of 0.3: 1, 0.5: 1, of 1 :1, of 1.5: 1, of 2: 1, of 2.5: 1, and of 3: 1.
- At least one N-acetyl amino acid amide and at least one additional compound are in molar ratio of 1 : 1.
- At least two N-acetyl amino acid amides may form a deep eutectic solvent (DES).
- at least one N-acetyl amino acid amide and at least one additional compound may form a deep eutectic solvent. It is noticed that in case that the deep eutectic solvent has been formed, the pharmaceutical formulation according to the present description is having improved stability over time.
- deep eutectic solvent a solvent prepared with a combination of two or more solid substances which have melting point above room temperature, which substances, when mixed in appropriate proportions, give rise to a liquid mixture at room temperature.
- Solid substances which can be combined in deep eutectic solvent are selected from organic acids, sugars, sugar alcohols, amines, amides and amino acids.
- water may be added in an amount from 0% w/V to 50 % w/V of water.
- the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are comprised in the pharmaceutical formulation in the form of deep eutectic solvent.
- deep eutectic solvent is formed when the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio from 0.3 : 1 to 3 : 1.
- deep eutectic solvent is formed when the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio of 0.3: 1, of 0.5: 1, of 1 :1, of 1.5: 1, of 2: l, of 2.5: l, and of 3: l.
- deep eutectic solvent is formed when the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio of 1 : 1.
- deep eutectic solvent is formed when at least one N-acetyl amino acid amide and at least one additional compound are in molar ratio from 0.3 : 1 to 3 : 1.
- deep eutectic solvent is formed when at least one N-acetyl amino acid amide and at least one additional compound are in molar ratio of 0.3: 1, 0.5: 1, of 1 : 1, of 1.5: 1, of 2: 1, of 2.5: 1, and of 3: 1.
- deep eutectic solvent is formed when at least one N-acetyl amino acid amide and at least one additional compound are in molar ratio of 1 : 1.
- deep eutectic solvents may comprise 50% w/V or less of water.
- deep eutectic solvents may contain 45% or less, of 40% w/V or less, 35% w/V or less, 30% w/V or less, 25% w/V or less, 20% w/V or less, 15% w/V or less, 10% w/V or less, 5% w/V or less, 2% w/V or less of water.
- deep eutectic solvent in accordance with this disclosure may comprise from 20% w/V to 50% w/V of water.
- deep eutectic solvent in accordance with this disclosure may comprise from 20% w/V to 40% w/V of water.
- deep eutectic solvent in accordance with this disclosure may comprise 40% w/V of water.
- molar ratio of each of N-acetyl amino acid amides in formulation to total of active pharmaceutical ingredients in the formulation is from 1 : 1 to 300: 1.
- molar ratio of each of N-acetyl amino acid amides in formulation to total of active pharmaceutical ingredients in the formulation is from 1 : 1 to 160: 1.
- molar ratio of each of N-acetyl amino acid amides in formulation to total of active pharmaceutical ingredients in the formulation is from 1 : 1 to 50: 1.
- molar ratio of each of N-acetyl amino acid amides to total of piperacillin and tazobactam is from 1 : 1 to 40: 1.
- molar ratio of each of N-acetyl amino acid amides to total of piperacillin and tazobactam is from 10: 1 to 30: 1.
- molar ratio of each of N-acetyl amino acid amides to total of piperacillin and tazobactam is 26: 1.
- molar ratio of each of N- acetyl amino acid amides in the formulation to piperacillin is from 30: 1 to 60: 1.
- molar ratio of each of N- acetyl amino acid amides in the formulation to tazobactam is from 100: 1 to 300: 1.
- pharmaceutical formulation further comprises buffering and/or chelating agents.
- buffering agents may be selected separately or in combination comprise MES (2-(N-morpholino)ethanesulfonic acid), maleate, malate, phosphate, carbonate, citrate, tartrate, succinate, oxalate, ADA (N-(2- Acetamido)iminodiacetic acid), BIS TRIS (2-[Bis-(2-hydroxy-ethyl)-amino]-2- hydroxymethyl-propane- 1,3 -diol), PIPES (1,4-Piperazinedi ethanesulfonic acid), ACES (N-(2-Acetamido)-2-aminoethanesulfonic acid), BIS TRIS propane (2-[3-(2- Hydroxy- 1 , 1 -dihydroxymethyl -ethylamino)-propylamino]-2-hydroxymethyl- propane- 1,3 -diol), MOPSO (2 -Hydroxy-3
- TAPSO 3-[[l,3-dihydroxy-2- (hydroxymethyl)propan-2-yl]amino]-2-hydroxypropane-l-sulfonic acid), TEA (triethanolamine), HEPPSO (2 -Hydroxy-3 -(4-(2 -hydroxy ethyl)piperazin-l - yl)propane-l -sulfonic acid), HEPPS (3-[4-(2-Hydroxyethyl)piperazin-l-yl]propane- 1 -sulfonic acid), POPSO (Piperazine- l,4-bis(2-hydroxypropanesulfonic acid), Tricine (N-Tris(hydroxymethyl)methylglycine), Tris
- buffers may also act as chelating agents, i.e. citrate buffer, ADA, BIS TRIS; BIS TRIS propane, AMPD; AMP, AMPSO, TABS, ACES, BES, TES, DIPSO; TAPSO, TRIS, TEA, Tricine, Bicine, TAPS, tartaric acid, , succinic acid, oxalic acid, malic acid etc.
- non-exhaustive list from which chelating agents may be selected separately or in combination comprise Dimethyl methylphosphonate, Diethylenetriamine pentamethylene phosphonic acid, Diethyl allylphosphonate, Diethyl (l-cyanoethyl)phosphonate, Nitrilotri (methylphosphonic acid), N-(2- Hydroxyethyl)iminodiacetic acid, Ethylenediamine-N,N'-disuccinic acid trisodium salt solution, Iminodiacetic acid, Disodium succinate, Sodium gluconate, 15-Crown- 5 ether, 18-Crown-6 ether, DOTA (1,4,7, 10-Tetraazacyclododecane-l,4,7, 10- tetraacetic acid), NOTA (l,4,7-triazacyclononane-l,4,7-triacetic acid) and derivatives thereof.
- the buffering agent is citrate buffer.
- the buffering agent is ADA.
- the buffering agent is citrate buffer and ADA.
- the concentration of buffering agent would be from 0.5 mM to 200 mM.
- the concentration of buffering agent would be from 10 mM to 25 mM.
- the buffer is prepared at pH 5.5 to 8.
- the buffer is prepared at pH 6 to 6.5.
- the concentration of chelating agent would be from 0.1 mM to 200 mM.
- the concentration of chelating agent would be from 10 mM to 25 mM.
- the compositions may be in form of a ready-to-administer or a ready-to-use composition.
- ready-to-use includes liquid preconcentrates which require a single step of dilution with a liquid diluent fluid such as water for injection or saline before administration.
- a "ready -to-administer” composition is synonymous with "ready -to-infuse” or “ready -to-inject” and is not to be read as the term “ready -to-use” composition.
- a “ready -to-administer” composition is suitable for administration directly to the patient and does not require any dilution steps.
- ready-to-administer is also distinguished from lyophilized products that require two steps, a first step of reconstitution to form a preconcentrate and then a second step where the preconcentrate is subjected to dilution with a liquid infusion fluid.
- Suitable fluids for diluting the ready -to-use composition include some which are pharmaceutical; safe and non-toxic for administration to a human, and are compatible for the preparation of a diluted formulation.
- pharmaceutical formulation can be diluted with water or some diluents for oral use, standard diluents for parenteral use, such as water for injection, 0.9% sodium chloride for injection, Sterile water for injection, Dextrose 5% injection, Bacteriostatic saline/parabens, Bacteriostatic water/parabens, Bacteriostatic saline/benzyl alcohol, Bacteriostatic water/benzyl alcohol, Ringer’s solution or other suitable diluents.
- standard diluents for parenteral use such as water for injection, 0.9% sodium chloride for injection, Sterile water for injection, Dextrose 5% injection, Bacteriostatic saline/parabens, Bacteriostatic water/parabens, Bacteriostatic saline/benzyl alcohol, Bacteriostatic water/benzyl alcohol, Ringer’s solution or other suitable diluents.
- the appropriate volume of the liquid formulation of the present invention needed for the required therapeutically effective dose can be aseptically withdrawn and transferred into an infusion bag of 0.9% Sodium Chloride, or of Sterile water for injection or of Bacteriostatic water for injection and administrated to a patient via appropriate route of administration.
- pharmaceutical formulation is having pH from 4.0 to 8.0.
- pharmaceutical formulation is having a pH range from 5.5 to 8.
- Formulations of the present disclosure comprise therapeutically effective amounts of active pharmaceutical ingredient, wherein therapeutically effective amounts include concentrations ranging from 0.05 mg/mL to 250 mg/mL 0.5 mg/mL to 250 mg/mL, from 20 mg/mL to 500 mg/mL, from 50 mg/mL to 300 mg/mL, such as concentration of 0.5 mg/mL, 1 mg/mL, 3 mg/mL, 5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, 190 mg/mL, 200 mg/mL, 210 mg/
- concentration of piperacillin in pharmaceutical formulation as described herein is 40 mg/mL.
- concentration of tazobactam pharmaceutical formulation as described herein is 5 mg/mL.
- This disclosure also provides method for stabilizing piperacillin and/or tazobactam in a pharmaceutical composition by mixing piperacillin and/or tazobactam and at least one N-acetyl amino acid amide.
- This disclosure also provides process for manufacturing pharmaceutical formulations disclosed herein.
- the process may comprise the steps of mixing of at least one active pharmaceutical ingredient and at least one N- acetyl amino acid amide.
- This disclosure also provides process for manufacturing any of the disclosed pharmaceutical formulations.
- the process may comprise the steps of mixing of active pharmaceutical ingredients and at least one N-acetyl amino acid amide, and subsequently dissolving composition in a solvent.
- process for manufacturing pharmaceutical formulations disclosed herein comprises mixing of at least one N-acetyl amino acid amide with a solvent. Prepared solution is then mixed with at least one active pharmaceutical ingredient.
- process for manufacturing pharmaceutical formulations disclosed herein comprises mixing of at least one N-acetyl amino acid amide with a second N-acetyl amino acid amide and/or an additional compound in a solvent. Prepared solution in then mixed with at least one active pharmaceutical ingredient. According to the described process, pharmaceutical formulations comprising deep eutectic solvent may be formed.
- At least one N-acetyl amino acid amide is mixed with the second N-acetyl amino acid amide and/or an additional compound to create a deep eutectic solvent.
- prepared deep eutectic solvents may comprise up to 50% w/V of water. Heating of mixture can be used until liquid is formed which is then cooled to room temperature. Prepared deep eutectic solvent is then mixed with at least one active pharmaceutical ingredient.
- pharmaceutical formulation may be manufactured by any process known to the person skilled in the art.
- solvent means water or any solution in which water is the main solvent (equal or above 50% w/V).
- Solvents include, but are not limited to solutions comprising at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98% or 99% w/V water.
- Solvents can comprise a pharmaceutical organic solvent like ethanol, glycerol, propylene glycol, polyethylene glycols.
- Solvents can comprise 50% w/V or less of a pharmaceutical organic solvent.
- pH is the conventional measurement unit of hydrogen ion activity in a solution at room temperature, unless another temperature is specified.
- pH buffer or “buffer” means a compound or composition used to maintain the pH value or pH range of a formulation within desired parameters over time.
- pH buffers include aqueous solutions comprising a mixture of a weak acid and its conjugate base (or a weak base and its conjugate acid). The pH of a buffered solution changes very little when a small amount of an acid or base is added to it. A non-exhaustive list of pH buffers are mentioned above.
- pharmaceutical composition comprises piperacillin sodium and at least one N-acetyl amino acid amide.
- pharmaceutical composition comprises piperacillin sodium and at least two N-acetyl amino acid amides.
- pharmaceutical composition comprises piperacillin sodium and N- Acetyl-L-alaninamide.
- pharmaceutical composition comprises piperacillin sodium and N- acety 1 -D -al aninami de .
- pharmaceutical composition comprises piperacillin sodium and N- acetyl-L-prolinamide.
- pharmaceutical composition comprises piperacillin sodium, N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
- pharmaceutical composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide.
- pharmaceutical composition comprises piperacillin sodium, N- acetyl-L-prolinamide and N-acetyl-D-alaninamide.
- pharmaceutical composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D- alaninamide.
- pharmaceutical composition comprises piperacillin sodium, N- acetyl-L-prolinamide and N-acetyl-D-alaninamide, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of from 0.3 : 1 to 3 : 1.
- pharmaceutical composition comprises piperacillin sodium, N- acetyl-L-prolinamide and N-acetyl-D-alaninamide, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1.
- pharmaceutical composition comprises piperacillin sodium, N- acetyl-L-prolinamide and N-acetyl-D-alaninamide, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and where molar ratio of each said N-acetyl amino acid amides to piperacillin is from 30: 1 to 50: 1.
- pharmaceutical composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D- alaninamide, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and where molar ratio of each said N-acetyl amino acid amides to piperacillin is 32: 1.
- pharmaceutical composition comprises piperacillin sodium, N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of from 0.3: 1 to 3 : 1.
- pharmaceutical composition comprises piperacillin sodium, N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1.
- pharmaceutical composition comprises piperacillin sodium, N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where molar ratio of each said N-acetyl amino acid amides to piperacillin is from 30: 1 to 50: 1.
- pharmaceutical composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where molar ratio of each said N-acetyl amino acid amides to piperacillin is 32: 1.
- composition comprises piperacillin sodium, N- acetyl-L-prolinamide and N-acetyl-D-alaninamide and water, where N-acetyl-L- prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in less than 50% w/V of total composition.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D-alaninamide and water, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total composition.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D-alaninamide and water, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1, where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N-acetyl amino acid amides to piperacillin is from 30: 1 to 50: 1.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-acetyl-L-prolinamide and N- acetyl-D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total composition.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D- alaninamide, water and buffering and/or chelating agent, where N-acetyl-L- prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 , where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N-acetyl amino acid amides to piperacillin is from 30: 1 to 50: 1.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-acetyl-L-prolinamide and N- acetyl-D-alaninamide are in molar ratio of 1 : 1, where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N- acetyl amino acids amide to piperacillin is 32: 1.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D- alaninamide, water and a citric buffer, where N-acetyl-L-prolinamide and N-acetyl- D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total composition.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-acetyl-D-alaninamide, water and ADA, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total composition.
- composition comprises piperacillin sodium, N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide and water, where N-acetyl-L- prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in less than 50% of total composition.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide and water, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total composition.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide and water, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1, where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N-acetyl amino acid amides to piperacillin is from 30: 1 to 50: 1.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide and water, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1, where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N-acetyl amino acid amides to piperacillin is 32: 1.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide, water and buffering and/or chelating agent, where N-acetyl-L- prolinamide and N-acetyl-L-alaninamide are in molar ratio of 1 : 1, where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N-acetyl amino acid amides to piperacillin is from 30: 1 to 50: 1.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-acetyl-L-prolinamide and N- Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total composition.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-acetyl-L-prolinamide and N- Acetyl-L-alaninamide are in molar ratio of 1: 1, where composition comprises water in an amount of 40% w/V of total composition and where molar ratio of each said N- acetyl amino acid amides to piperacillin is 32: 1.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide, water and citric buffer, where N-acetyl-L-prolinamide and N-Acetyl- L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total composition.
- composition comprises piperacillin sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and ADA, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises tazobactam sodium and at least one N-acetyl amino acid amide.
- composition comprises tazobactam sodium and at least two N-acetyl amino acid amides.
- pharmaceutical composition comprises tazobactam sodium and N- Acetyl-L-alaninamide.
- pharmaceutical composition comprises tazobactam sodium and N- acety 1 -D -al aninami de .
- pharmaceutical composition comprises tazobactam sodium and N- acetyl-L-prolinamide.
- composition comprises tazobactam sodium, N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
- pharmaceutical composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide.
- pharmaceutical composition comprises tazobactam sodium, N- acetyl-L-prolinamide and N-acetyl-D-alaninamide.
- pharmaceutical composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D- alaninamide.
- pharmaceutical composition comprises tazobactam sodium, N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of from 0.3: 1 to 3 : 1.
- pharmaceutical composition comprises tazobactam sodium, N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1.
- pharmaceutical composition comprises tazobactam sodium, N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where molar ratio of each said N-acetyl amino acid amides to tazobactam is from 150:1 to 220:1.
- pharmaceutical composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where molar ratio of each said N-acetyl amino acid amides to tazobactam is 153: 1.
- pharmaceutical composition comprises tazobactam sodium, N- acetyl-L-prolinamide and N-acetyl-D-alaninamide, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of from 0.3: 1 to 3 : 1.
- pharmaceutical composition comprises tazobactam sodium, N- acetyl-L-prolinamide and N-acetyl-D-alaninamide, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1.
- pharmaceutical composition comprises tazobactam sodium, N- acetyl-L-prolinamide and N-acetyl-D-alaninamide, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and where molar ratio of each said N-acetyl amino acid amides to tazobactam is from 150: 1 to 220:1.
- pharmaceutical composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D- alaninamide, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and where molar ratio of each said N-acetyl amino acid amides to tazobactam is 153: 1.
- composition comprises tazobactam sodium, N- acetyl-L-prolinamide and N-acetyl-D-alaninamide and water, where N-acetyl-L- prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in less than 50% of total composition.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D-alaninamide and water, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D-alaninamide and water, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N-acetyl amino acid amides to tazobactam is from 150: 1 to 220: 1.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D-alaninamide and water, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N-acetyl amino acid amides to tazobactam is from 153: 1.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-acetyl-L-prolinamide and N- acetyl-D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-acetyl-L-prolinamide and N- acetyl-D-alaninamide are in molar ratio of 1 : 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N- acetyl amino acid amides to tazobactam is from 150: 1 to 220: 1.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-acetyl-L-prolinamide and N- acetyl-D-alaninamide are in molar ratio of 1 : 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N- acetyl amino acid amides to tazobactam is from 153: 1.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D- alaninamide, water and citric buffer, where N-acetyl-L-prolinamide and N-acetyl-D- alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-acetyl-D-alaninamide, water and ADA, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises tazobactam sodium, N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide and water, where N-acetyl-L- prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where water is comprised in less than 50% of total volume of the formulation.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide and water, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide and water, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N-acetyl amino acid amides to tazobactam is from 150: 1 to 220:1.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide and water, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N-acetyl amino acid amides to tazobactam is from 153: 1.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-acetyl-L-prolinamide and N- Acetyl-L-alaninamide are in molar ratio of 1 : 1 and were composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-acetyl-L-prolinamide and N- Acetyl-L-alaninamide are in molar ratio of 1: 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N- acetyl amino acid amides to tazobactam is from 150: 1 to 220: 1.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-acetyl-L-prolinamide and N- Acetyl-L-alaninamide are in molar ratio of 1: 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each said N- acetyl amino acid amides to tazobactam is from 153: 1.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide, water and citric buffer, where N-acetyl-L-prolinamide and N-Acetyl- L-alaninamide are in molar ratio of 1 : 1 and were composition comprises water in an amount of 40% w/V of total formulation.
- pharmaceutical composition comprises tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N-Acetyl-L-alaninamide, water and ADA, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and were composition comprises water in an amount of 40% w/V of total formulation.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and at least one N-acetyl amino acid amide.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and at least two N-acetyl amino acid amides.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and at least two N-acetyl amino acid amides, where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is from 10: 1 to 30: 1.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and N-Acetyl-L-alaninamide.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and N-acetyl-D-alaninamide.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and N-acetyl-L-prolinamide.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-acetyl-L-prolinamide and N-acetyl-D-alaninamide.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D-alaninamide.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-acetyl-L-prolinamide and N-acetyl-D-alaninamide, where N- acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of from 0.3: 1 to 3: 1.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-acetyl-L-prolinamide and N-acetyl-D-alaninamide, where N- acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-acetyl-L-prolinamide and N-acetyl-D-alaninamide, where N- acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D-alaninamide, where N-acetyl-L-prolinamide and N-acetyl-D- alaninamide are in molar ratio of 1 : 1 and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of from 0.3:1 to 3: 1.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
- pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide, where N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide are in molar ratio of 1 : 1 and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
- composition comprises piperacillin sodium and tazobactam sodium and N-acetyl-L-prolinamide and N-acetyl-D-alaninamide and water, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in less than 50% of total volume of the formulation.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D-alaninamide and water, where N-acetyl-L-prolinamide and N-acetyl-D- alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D-alaninamide and water, where N-acetyl-L-prolinamide and N-acetyl-D- alaninamide are in molar ratio of 1 : 1, composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N- acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-acetyl-L- prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and were composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N- acetyl-D-alaninamide, water and buffering and/or chelating agent, where N-acetyl-L- prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1, composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D-alaninamide, water and citric buffer, where N-acetyl-L-prolinamide and N-acetyl-D-alaninamide are in molar ratio of 1 : 1 and were composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D-alaninamide, water and citric buffer, where piperacillin and tazobactam are comprised in weight ratio 8: 1, where N-acetyl-L-prolinamide and N-acetyl-D- alaninamide are in molar ratio of 1 : 1 and were composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N- acetyl-D-alaninamide, water and ADA, where N-acetyl-L-prolinamide and N-acetyl- D-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D-alaninamide, water and ADA, where piperacillin and tazobactam are comprised in weight ratio 8: 1, where N-acetyl-L-prolinamide and N-acetyl-D- alaninamide are in molar ratio of 1 : 1 and were composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises piperacillin sodium and tazobactam sodium and N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide and water, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in less than 50% of total volume of the formulation.
- pharmaceutical composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide and water, where N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide and water, where N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide are in molar ratio of 1 : 1, composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N- Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-acetyl- L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N- Acetyl-L-alaninamide, water and buffering and/or chelating agent, where N-acetyl- L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1, composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
- pharmaceutical composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide, water and citric buffer, where N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide, water and citric buffer, where piperacillin and tazobactam are comprised in weight ratio 8: 1, where N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- pharmaceutical composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide, water and citric buffer, where piperacillin and tazobactam are comprised in weight ratio 8: 1, where N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide are in molar ratio of 1 : 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N- Acetyl-L-alaninamide, water and ADA, where N-acetyl-L-prolinamide and N- Acetyl-L-alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- pharmaceutical composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N- Acetyl-L-alaninamide, water and ADA, where piperacillin and tazobactam are comprised in weight ratio 8: 1, where N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide are in molar ratio of 1 : 1 and where composition comprises water in an amount of 40% w/V of total formulation.
- composition comprises piperacillin sodium and tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide, N- Acetyl-L-alaninamide, water and ADA, where piperacillin and tazobactam are comprised in weight ratio 8: 1, where N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide are in molar ratio of 1 : 1, where composition comprises water in an amount of 40% w/V of total formulation and where molar ratio of each N-acetyl amino acid amide to total of piperacillin and tazobactam is 26: 1.
- the disclosure also relates to the packaging any of the above pharmaceutical formulations.
- the liquid pharmaceutical formulation may be packaged in a bag ready to be administered to a patient. Further, the formulation may be packaged in dual chamber bag or syringe.
- liquid pharmaceutical formulation may be packaged in a vial or ampoule for dilution prior to administration a patient.
- pharmaceutical formulation may be packaged for oral administration in form of oral suspension or oral solution.
- pharmaceutical formulation may be packaged for topical administration in form of gel.
- the pharmaceutical formulation may be used in the treatment of microbial infections caused by Gram positive bacteria, and in some cases for treatment of microbial infections caused by Gram negative bacteria.
- the formulation comprises piperacillin and tazobactam and may be used in treatment of for the treatment of appendicitis (complicated by rupture or abscess) and peritonitis caused by piperacillin-resistant, beta-lactamase producing isolates of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis, B. ovatus, B. thetaiotaomicron, or B.
- nosocomial pneumonia caused by piperacillin-resistant, beta-lactamase producing isolates of Staphylococcus aureus and by piperacillin/tazobactam- susceptible Acinetobacter baumannii, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa, uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by piperacillin-resistant, beta-lactamase producing isolates of Staphylococcus aureus, postpartum endometritis or pelvic inflammatory disease caused by piperacillin-resistant, beta-lactamase producing isolates of Escherichia coli, and community-acquired pneumonia (moderate severity only) caused by piperacillin-resistant, beta-lactamase producing isolates of Haemophilus influenzae.
- piperacillin or piperacillin/tazobactam are used for treating against variety of gram-positive and gram-negative aerobic and anaerobic bacteria.
- the use of pharmaceutical formulation of piperacillin in accordance with the present invention is for treating the gram-positive pathogens such as Staphylococcus aureus, or intra - abdominal infections, skin and skin structure infections, female pelvic infections, community - acquired pneumonia, nosocomial pneumonia.
- compositions as disclosed herein may be used for prevention of biofilm as well as for treating already formed biofilms.
- therapeutically effective amount of the pharmaceutical formulation refers to an amount of active pharmaceutical ingredient administered to a patient sufficient to produce a therapeutic response to one or more of the symptoms of the disease being treated.
- formulations described herein are intended to be administered via injection, for example subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intrasynovially, intrasternally, intrathecally, intralesionally, intracranially or via infusion.
- formulations described herein may be administered orally, topically.
- formulation described herein are used topically. In an aspect, formulation described herein may be used topically for treatment of skin and soft tissue infections caused by Staphylococcus aureus. In an aspect, formulation described herein may be used topically for treatment of skin infections caused by Methicillin-resistant Staphylococcus aureus (MRSA), Methicillin-susceptible Staphylococcus aureus (MS SA).
- MRSA Methicillin-resistant Staphylococcus aureus
- MS SA Methicillin-susceptible Staphylococcus aureus
- molar ratios and concentrations of ingredients comprised in the pharmaceutical formulation and solvents are defined by the amount of said ingredients used for production of said pharmaceutical formulation.
- compositions described herein may further comprise one or more pharmaceutical excipients such as antioxidants, surfactants, complexing agents, preservatives, bulking agents, vehicles, solubilizers, thickening agents, binders, and combinations thereof.
- pharmaceutical excipients such as antioxidants, surfactants, complexing agents, preservatives, bulking agents, vehicles, solubilizers, thickening agents, binders, and combinations thereof.
- API Active pharmaceutical ingredient
- containers were taken from stability chambers at various time points, such as 4 days, 7 days, 8 days, 11 days, 14 days, 22 days, 1 month, 2 months, 3 months, 4 months etc. and analyzed by HPLC.
- the impurities for active compounds and amount of total impurities were determined by HPLC analysis, equipped with an ultraviolet (UV) detector. All samples were analyzed using a reverse-phase C18 column and by measuring the absorbance (area under the curve) at a wavelength of 220 nm.
- the HPLC conditions used were those disclosed in the Official Monographs/ Piperacillin, USP 40, pages 5731-5734, Piperacillin and Tazobactam for Injection, Impurities, procedure 3 and 4 with some modifications (disclosed below).
- Injection volume 20 pL/2pL (depending on the sample dilution)
- Buffer 27.6 g/L of monobasic sodium phosphate dihydrate
- Solution A 0.4 M aqueous tetrabutylammonium hydroxide
- Solution B Methanol, Solution A, Buffer, and water (275:3: 100:622). Adjust with phosphoric acid to a pH of 5.5 ⁇ 0.05.
- Solution C Methanol, Solution A, Buffer, and water (615:3: 100:282). Adjust with phosphoric acid to a pH of 5.5 ⁇ 0.05.
- Mobile phase See Table
- Sample solution preparation for formulation comprising deep eutectic solvent ImL of the formulation is dissolved in mobile phase A and diluted to 10.0 mL with mobile phase A.
- Buffer 4.46 g/L of potassium phosphate monobasic
- Solution A buffer Solution B: Acetonitrile and Solution A (550:450). Adjust with IM potassium hydroxide to a pH of 6.0 ⁇ 0.05.
- Sample solution ImL of the formulation dissolved in buffer and diluted to 10.0 mL with buffer.
- Atot total sample peak area (for each active component separately, area of the main peak + areas of all impurities related to this active compound) Calculation of the purity drop of the main peak
- a Pmpp(%) Pmp(st) (%) - Pmp(tp)(%)
- Ai peak area of an individual peak
- Atot total sample peak area (for each active component separately, area of the main peak + areas of all impurities related to this active compound)
- APIs are added in a form of sodium salts (Piperacillin sodium equivalent to concentration of Piperacillin stated in the tables; Tazobactam sodium equivalent to concentration of Tazobactam stated in the tables).
- Liquid pharmaceutical compositions of piperacillin sodium and N-acetyl amino acid amides were prepared in predetermined concentrations and in certain compositions (as shown below). N-acetyl amino acid amides were mixed with water and optionally with a buffer. After that, piperacillin sodium is mixed with liquid containing N-acetylated amino acid amides in the molar ratios specified in Table 1 below, until the substances were dissolved. Water was added to make the solution up to the prescribed volume and stirred to give homogenous solution with the concentration of 40 mg/ml of piperacillin.
- Tables la and lb are showing stability data of Piperacillin sodium formulations prepared by above described process.
- Liquid pharmaceutical compositions of tazobactam sodium and N-acetyl amino acid amides were prepared in predetermined concentrations and in certain compositions (as shown below). N-acetyl amino acid amides are mixed with water and optionally with a buffer. After that, tazobactam sodium is mixed with liquid containing N-acetylated amino acid amides in the molar ratios specified in Table 2 below, until the substances
- Liquid pharmaceutical compositions of piperacillin sodium, tazobactam sodium and N- acetyl amino acid amides were prepared in certain compositions (as shown below). N- acetyl amino acid amides are mixed with water and optionally with a buffer. After that, tazobactam sodium and piperacillin sodium were mixed with liquid containing N- acetylated amino acid amide in the molar ratios specified in Table 3 below, until the substances were dissolved. Water was added to make the solution up to the prescribed volume and stirred to give homogenous solution with the concentration of 40 mg/ml of piperacillin and 5 mg/ml of tazobactam.
- Tables 3a and 3b are showing stability data of Piperacillin sodium and Tazobactam sodium formulations prepared by above described process. Molar ratio of two N-acetyl amino acid amides is 1:1.
- Liquid pharmaceutical compositions of piperacillin sodium and N-acetyl amino acid amides were prepared in certain compositions (as shown below). N-acetyl amino acid amides and water/buffers were mixed in a bottle. Bottle was closed and mixing continued in oil bath heated to 60-70°C until liquid was formed. Formed liquid is then cooled to room temperature in order to prepare deep eutectic solvents. Part of volume of DES was mixed with piperacillin sodium until the substance was dissolved. After that, DES was added to make the solution up to the prescribed volume and stirred to give homogenous solution with the concentration of 40 mg/ml of piperacillin.
- Tables 4a and 4b are showing stability data of Piperacillin sodium DES formulations prepared by above described process. Molar ratio of two N-acetyl amino acid amides is 1:1. Buffers prepared in pH range of 6 - 6.5.
- Liquid pharmaceutical compositions of tazobactam and N-acetyl amino acid amides were prepared in certain compositions (as shown below). N-acetyl amino acid amides and water/buffers were mixed in a bottle. Bottle was closed and mixing continued in oil bath heated to 60-70°C until liquid was formed. Formed liquid is then cooled to room temperature in order to prepare deep eutectic solvents. Part of volume of DES was mixed with tazobactam sodium until the substance was dissolved. After that, DES was added to make the solution up to the prescribed volume and stirred to give homogenous solution with the concentration of 5 mg/ml of tazobactam.
- Table 5 is showing stability data of Tazobactam sodium DES formulations prepared by above described process. Molar ratio of two N-acetyl amino acid amides is 1 : 1. Buffers prepared in pH range of 6 - 6.5.
- Liquid pharmaceutical compositions of piperacillin sodium, tazobactam sodium and N- acetyl amino acid amides were prepared in certain compositions (as shown below). N- acetyl amino acid amides and water/buffers were mixed in a bottle. Bottle was closed and mixing continued in oil bath heated to 50-70°C until liquid was formed. Formed liquid is then cooled to room temperature in order to prepare deep eutectic solvents. Part of volume of DES was mixed with tazobactam sodium and piperacillin sodium until the substances were dissolved. After that, DES was added to make the solution up to the prescribed volume and stirred to give homogenous solution with the concentration of 40 mg/ml of piperacillin and 5 mg/ml of tazobactam.
- Tables 6a and 6b are showing stability data of Piperacillin sodium and Tazobactam sodium DES formulations prepared by above described process. Molar ratio of two N- acetyl amino acid amides is 1:1. Buffers prepared in pH range of 6 - 6.5.
- Liquid pharmaceutical compositions of piperacillin sodium, tazobactam sodium and N- acetyl amino acid amides were prepared in certain compositions (as shown below).
- N- acetyl amino acid amides and water/buffers were mixed in a bottle. Bottle was closed and mixing continued in oil bath heated to 50-70°C until liquid was formed. Formed liquid is then cooled to room temperature in order to prepare deep eutectic solvents.
- Molar ratio of two N-acetyl amino acid amides in DES is 1:1.
- DES also comprises citric buffer in molar ratio 1 :250 to each N-acetyl amino acid amide and 40 % wfV of water.
- piperacillin sodium and tazobactam sodium are mixed with liquid containing N-acetylated amino acid amides in the molar ratios specified in Table 7 below. Additional amount of water or buffer is added and mixing continued until the substances were dissolved. Water or buffer was added to make the solution up to the prescribed volume and stirred to give homogenous solution with the concentration of 40 mg/ml of piperacillin and 5 mg/ml of tazobactam.
- Tables 7a and 7b are showing stability data of Piperacillin sodium and Tazobactam sodium formulation - diluted stream.
- Item 1 A pharmaceutical formulation comprising at least piperacillin and/or tazobactam, its salt or derivative thereof and at least one N-acetyl amino acid amide.
- Item 2. The pharmaceutical formulation according to item 1, wherein pharmaceutical formulation comprises piperacillin, salt or derivative thereof.
- Item 3 The pharmaceutical formulation according to item 1, wherein pharmaceutical formulation comprises tazobactam, its pharmaceutical salt or derivative thereof.
- SUBSTITUTE SHEET (RULE 26) Item 4.
- Item 5 The pharmaceutical formulation according to item 3, wherein the formulation comprises at least one beta-lactam antibiotic and tazobactam.
- Item 6 The pharmaceutical formulation according to item 1, wherein the formulation comprises piperacillin and tazobactam, its pharmaceutical salt or derivative thereof.
- Item 7 The pharmaceutical formulation according to item 1, wherein piperacillin and/or tazobactam is in form of a salt, where salt may include calcium, sodium, magnesium or potassium salt.
- Item 8 The pharmaceutical formulation according to item 7, wherein piperacillin and/or tazobactam is in form of sodium salt.
- Item 9 The pharmaceutical formulation according to item 8, wherein piperacillin is in form of sodium salt.
- Item 10 The pharmaceutical formulation according to item 8, wherein tazobactam is in form of sodium salt.
- Item 11 The pharmaceutical formulation according to item 6, wherein weight ratio of piperacillin to tazobactam can be from 4: 1 to 8: 1.
- Item 12 The pharmaceutical formulation according to item 6, wherein weight ratio of piperacillin to tazobactam is 8:1.
- N-acetyl amino acid amide may be N-acetyl cysteinamide, N-acetyl glutaminamide, N-acetyl aspartic acid amide, N-acetyl glycinamide, N-acetyl alaninamide, N-acetyl prolinamide, N-acetyl serinamide, N-acetyl threoninamide, N-acetyl valinamide, N-acetyl isoleucinamide, N- Acetyl leucinamide, N-acetyl methioninamide, N-acetyl phenylalaninamide, N-acetyl tyrosinamide, N-acetyl asparaginamide, N-acetyl glutamic acid amide, N-acetyl histidinamide, N-acetyl argininamide, N-acetyl citrullinamide, N-
- N-acetyl amino acid amide may be in L configuration, while in some other aspect N-acetyl amino acid amide may be in D configuration.
- SUBSTITUTE SHEET (RULE 26) Item 15.
- NALAA N-Acetyl-L-alaninamide
- NADAA N-acetyl-D-alaninamide
- NALPA N-Acetyl-L-prolinamide
- Item 18 The pharmaceutical formulation according to item 1, wherein a concentration of an N-acetyl amino acid amide is from 1 mg/ml to 1500 mg/ml.
- Item 19 The pharmaceutical formulation according to item 18, wherein concentration of an N-acetyl amino acid amide is from 20 mg/ml to 1000 mg/ml.
- Item 20 The pharmaceutical formulation according to item 18, wherein concentration of each N-acetyl amino acid amide is 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 150 mg/ml, 200 mg/ml, 250 mg/ml, 300 mg/ml, 400 mg/ml, 500 mg/ml, 600 mg/ml, 700 mg/ml, 750 mg/ml, 800 mg/ml.
- Item 21 The pharmaceutical formulation according to item 18, wherein concentration of an N-acetyl amino acid amide is from 300 mg/ml to 750mg/ml.
- Item 22 The pharmaceutical formulation according to item 1, wherein formulation comprises at least two N-acetyl amino acid amides, i.e. a first and a second N-acetyl amino acid amide.
- Item 23 The pharmaceutical formulation according to item 22, wherein pharmaceutically acceptable formulation comprises N-acetyl-L-prolinamide and N- Acetyl-L-alaninamide .
- Item 24 The pharmaceutical formulation according to item 22, wherein pharmaceutically acceptable formulation comprises N-acetyl-L-prolinamide and N- acetyl-D-alaninamide.
- Item 25 The pharmaceutical formulation according to item 22, wherein concentration of each amide is from 300 mg/ml to 600 mg/ml.
- Item 26 The pharmaceutical formulation according to item 22, wherein concentration of each amide is from 300 to 400 mg/ml.
- SUBSTITUTE SHEET (RULE 26) Item 27.
- Item 28 The pharmaceutical formulation according to item 22, wherein the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio of 0.2:1, 0.3:1, 0.4:1, 0.5:1, of 1:1, of 1.5:1, of2:l, of 2.5:1, of3:l, of 4:1, of 5:1.
- Item 29 The pharmaceutical formulation according to item 22, wherein, the first N- acetyl amino acid amide and the second N-acetyl amino acid amide are in molar ratio of 1:1.
- Item 30 The pharmaceutical formulation according to item 22, wherein the first N-acetyl amino acid amide and the second N-acetyl amino acid amide are comprised in the pharmaceutically acceptable formulation in the form of deep eutectic solvent.
- Item 31 The pharmaceutical formulation according to item 30, wherein the first N- acetylated amino acid amide and the second N-acetylated amino acid amide are in molar ratio from 0.3:1 to 3:1.
- Item 32 The pharmaceutical formulation according to item 30, wherein the first N- acetylated amino acid amide and the second N-acetylated amino acid amide are in molar ratio of0.3:l, of0.5:l, of 1:1, of 1.5:1, of2:l, of2.5:l, and of 3:1.
- Item 33 The pharmaceutical formulation according to item 30, wherein the first N- acetylated amino acid amide and the second N-acetylated amino acid amide are in molar ratio of 1:1.
- Item 34 The pharmaceutical formulation according to item 1, wherein formulation comprises additional compounds selected from nicotinamide, acetamide, benzamide, amino acids, quaternary ammonium compounds, quaternary phosphonium compounds, organic acids, sugars, urea and derivatives thereof, metal salts, choline chloride, sorbitol, ethyleneglylcol amide, polymers such as PEG, PPG, phenol, glycerol, saccharin, imidazole, its salts or derivatives thereof.
- additional compounds selected from nicotinamide, acetamide, benzamide, amino acids, quaternary ammonium compounds, quaternary phosphonium compounds, organic acids, sugars, urea and derivatives thereof, metal salts, choline chloride, sorbitol, ethyleneglylcol amide, polymers such as PEG, PPG, phenol, glycerol, saccharin, imidazole, its salts or derivatives thereof.
- Item 35 The pharmaceutical formulation according to item 34, wherein at least one N- acetylated amino acid amide and at least one additional compound are in molar ratio from 0.3:1 to 3:1.
- SUBSTITUTE SHEET (RULE 26) Item 36.
- Item 37 The pharmaceutical formulation according to item 34, wherein at least one N- acetylated amino acid amide and at least one additional compound are in molar ratio of 1:1.
- Item 38 The pharmaceutical formulation according to item 34, wherein the first N-acetyl amino acid amide and at least one additional compound are comprised in the pharmaceutical formulation in the form of deep eutectic solvent.
- Item 39 The pharmaceutical formulation according to item 34, wherein deep eutectic solvent is formed when the first N-acetyl amino acid amide and at least one additional compound are in molar ratio from 0.3:1 to 3 : 1.
- Item 40 The pharmaceutical formulation according to item 34, wherein deep eutectic solvent is formed when the first N-acetyl amino acid amide and at least one additional compound are in molar ratio of 0.3:1, of 0.5:1, of 1:1, of 1.5:1, of 2:1, of 2.5:1, and of 3:1.
- Item 41 The pharmaceutical formulation according to item 34, wherein deep eutectic solvent is formed when the first N-acetyl amino acid amide and at least one additional compound are in molar ratio of 1 : 1.
- Item 42 The pharmaceutical formulation according to item 30 and 34, wherein deep eutectic solvents may comprise 50% w/V or less of water.
- Item 43 The pharmaceutical formulation according to item 42, wherein deep eutectic solvents may contain 45% or less, of 40% w/V or less, 35% w/V or less, 30% w/V or less, 25% w/V or less, 20% w/V or less, 15% w/V or less, 10% w/V or less, 5% w/V or less, 2% w/V or less of water.
- Item 43 The pharmaceutical formulation according to item 42, wherein deep eutectic solvent in accordance with this disclosure may comprise from 20% w/V to 50% w/V of water.
- Item 44 The pharmaceutical formulation according to item 1, wherein pharmaceutical formulation further comprises buffering and/or chelating agents.
- SUBSTITUTE SHEET (RULE 26) Item 45.
- Item 46 The pharmaceutical formulation according to item 44, wherein the buffering agent is ADA.
- Item 47 The pharmaceutical formulation according to item 44, wherein the buffering agent is citrate buffer and ADA.
- Item 48 The pharmaceutical formulation according to item 44, wherein the concentration of buffering and/or chelating agents would be from ImM to 200 mM.
- Item 49 The pharmaceutical formulation according to item 44, wherein the concentration of buffering and/or chelating agent would be from lOmM to 60 mM.
- Item 50 The pharmaceutical formulation according to item 44, wherein the buffering agent is prepared at pH 6 to 6.5.
- Item 51 The pharmaceutical formulation according to item 1, wherein pharmaceutical formulation is liquid.
- Item 52 The pharmaceutical formulation according to item 1, wherein pharmaceutical formulation may be oral suspension or solution.
- Item 53 The pharmaceutical formulation according to item 1, wherein pharmaceutical formulation comprises water.
- Item 54 The pharmaceutical formulation according to item 53, wherein water is comprised in concentration of less than 50% w/V.
- Item 55 The pharmaceutical formulation according to item 53, wherein pharmaceutical formulation comprises less than 45% w/V, 40% w/V, 35% w/V, 30% w /V, 25% w /V, 20% w /V, 15% w /V, 10% w /V, 8% w /V, 6% w /V, 4% w /V, 2% w IN, 1% w IN of water.
- Item 56 The pharmaceutical formulation according to item 53, wherein formulations can be further diluted.
- Item 57 The pharmaceutical formulation according to item 1, wherein pharmaceutical formulation is semisolid, like ointments, creams, gels, or pastes.
- Item 58 The pharmaceutical formulation according to item 57, wherein the semisolid composition is gel.
- SUBSTITUTE SHEET (RULE 26) Item 59.
- the pharmaceutical formulation according to item 1, wherein pharmaceutical formulation is intended to be administered via injection for example subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intrasynovially, intrastemally, intrathecally, intralesionally, intracranially or via infusion.
- Item 60 The pharmaceutical formulation according to item 1, wherein pharmaceutical formulation is administered orally, topically.
- Item 61 The pharmaceutical formulation according to item 1, wherein pharmaceutical composition comprises piperacillin sodium and at least one N-acetyl amino acid amide.
- Item 62 The pharmaceutical formulation according to item 2, wherein pharmaceutical composition comprises piperacillin sodium and at least two N-acetyl amino acid amides.
- Item 63 The pharmaceutical formulation according to item 13, wherein pharmaceutical composition comprises piperacillin sodium and N-Acetyl-L-alaninamide.
- Item 64 The pharmaceutical formulation according to item 13, wherein pharmaceutical composition comprises piperacillin sodium and N-acetyl-D-alaninamide.
- Item 65 The pharmaceutical formulation according to item 13, wherein pharmaceutical composition comprises piperacillin sodium and N-acetyl-L-prolinamide.
- Item 66 The pharmaceutical formulation according to item 22, wherein pharmaceutical composition comprises piperacillin sodium, N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide.
- Item 67 The pharmaceutical formulation according to item 30, wherein pharmaceutical composition comprises piperacillin sodium and a deep eutectic solvent formed by N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
- Item 68 The pharmaceutical formulation according to item 22, wherein pharmaceutical composition comprises piperacillin sodium, N-acetyl-L-prolinamide and N-acetyl-D- alaninamide.
- Item 69 The pharmaceutical formulation according to item 30, wherein pharmaceutical composition comprises piperacillin sodium and a deep eutectic solvent formed by N- acetyl-L-prolinamide and N-acetyl-D-alaninamide.
- Item 70 The pharmaceutical formulation according to item 1, wherein pharmaceutical composition comprises tazobactam sodium and at least one N-acetyl amino acid amide.
- SUBSTITUTE SHEET (RULE 26) Item 71.
- Item 73 The pharmaceutical formulation according to item 13, wherein pharmaceutical composition comprises tazobactam sodium and N-acetyl-D-alaninamide.
- Item 74 The pharmaceutical formulation according to item 13, wherein pharmaceutical composition comprises tazobactam sodium and N-acetyl-L-prolinamide.
- Item 75 The pharmaceutical formulation according to item 22, wherein pharmaceutical composition comprises tazobactam sodium, N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide.
- Item 76 The pharmaceutical formulation according to item 22, wherein pharmaceutical composition comprises tazobactam sodium, N-acetyl-L-prolinamide and N-Acetyl-L- alaninamide.
- Item 77 The pharmaceutical formulation according to item 30, wherein pharmaceutical composition comprises tazobactam sodium and deep eutectic solvent formed by N- acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
- Item 78 The pharmaceutical formulation according to item 22, wherein pharmaceutical composition comprises tazobactam sodium, N-acetyl-L-prolinamide and N-acetyl-D- alaninamide.
- composition comprises tazobactam sodium and deep eutectic solvent formed by N- acetyl-L-prolinamide and N-acetyl-D-alaninamide.
- Item 80 The pharmaceutical formulation according to item 6, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and at least one N-acetyl amino acid amide.
- Item 81 The pharmaceutical formulation according to item 22, wherein, pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and at least two N- acetyl amino acid amides.
- SUBSTITUTE SHEET (RULE 26) Item 82.
- Item 83 The pharmaceutical formulation according to item 13, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and N-acetyl-D- alaninamide.
- Item 84 The pharmaceutical formulation according to item 13, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and N-acetyl-L- prolinamide.
- Item 85 The pharmaceutical formulation according to item 22, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-acetyl-L- prolinamide and N-Acetyl-L-alaninamide.
- Item 86 The pharmaceutical formulation according to item 22, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium, N-acetyl-L- prolinamide and N-acetyl-D-alaninamide.
- Item 87 The pharmaceutical formulation according to item 30, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-Acetyl-L-alaninamide.
- Item 88 The pharmaceutical formulation according to item 30, wherein pharmaceutical composition comprises piperacillin sodium, tazobactam sodium and deep eutectic solvent formed by N-acetyl-L-prolinamide and N-acetyl-D-alaninamide.
- Item 89 The pharmaceutical formulation according to item 30, wherein molar ratio of each of N-acetyl amino acid amides in formulation to total of active pharmaceutical ingredients in the formulation is from 1:1 to 300:1.
- Item 90 The pharmaceutical formulation according to item 89, wherein formulation comprises piperacillin and tazobactam, molar ratio of each of N-acetyl amino acid amides to total of piperacillin and tazobactam is from 10:1 to 30:1.
- Item 91 The pharmaceutical formulation according to item 89, wherein formulation comprises piperacillin, molar ratio of each of N-acetyl amino acid amides in the formulation to piperacillin is from 30:1 to 60:1.
- SUBSTITUTE SHEET (RULE 26) Item 92.
- Item 93 The pharmaceutical formulation according to item 18, wherein concentration of an N-acetyl amino acid amide is 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml,
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
La présente invention concerne des compositions pharmaceutiques comprenant de la pipéracilline et/ou du tazobactam et au moins un amide d'acide aminé N-acétyle. De telles compositions offrent une bonne stabilité dans le temps. L'invention concerne également un procédé de traitement d'infections bactériennes chez un sujet par l'administration de l'une quelconque desdites compositions décrites ici, ainsi qu'un procédé de stabilisation de pipéracilline et/ou de tazobactam dans une composition pharmaceutique liquide par mélange de pipéracilline et/ou de tazobactam avec au moins un amide d'acide aminé N-acétyle.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA202001314 | 2020-11-20 | ||
DK202001314 | 2020-11-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022106630A1 true WO2022106630A1 (fr) | 2022-05-27 |
Family
ID=81708417
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2021/082324 WO2022106630A1 (fr) | 2020-11-20 | 2021-11-19 | Formulations stables comprenant de la pipéracilline et/ou du tazobactam |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2022106630A1 (fr) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040204372A1 (en) * | 2003-04-14 | 2004-10-14 | Wyeth Holdings Corporation | Compositions containing pipercillin and tazobactam sodium useful for injection |
US20060084639A1 (en) * | 2004-10-14 | 2006-04-20 | Wyeth | Compositions containing piperacillin and tazobactam useful for injection |
CN101129360A (zh) * | 2007-09-14 | 2008-02-27 | 刘力 | 易溶解的抗菌药物组合药物制剂、制备方法及用途 |
-
2021
- 2021-11-19 WO PCT/EP2021/082324 patent/WO2022106630A1/fr unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040204372A1 (en) * | 2003-04-14 | 2004-10-14 | Wyeth Holdings Corporation | Compositions containing pipercillin and tazobactam sodium useful for injection |
US20060084639A1 (en) * | 2004-10-14 | 2006-04-20 | Wyeth | Compositions containing piperacillin and tazobactam useful for injection |
CN101129360A (zh) * | 2007-09-14 | 2008-02-27 | 刘力 | 易溶解的抗菌药物组合药物制剂、制备方法及用途 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0832649B1 (fr) | Agent antifongique | |
US4829088A (en) | Medicament for the treatment of inflammations of the eye | |
US4728509A (en) | Aqueous liquid preparation | |
US9044485B2 (en) | Ceftolozane antibiotic compositions | |
US20180104338A1 (en) | Ceftolozane antibiotic compositions | |
FR2853547A1 (fr) | Compositions pharmaceutiques injectables contenant de la piperacilline et du tazobactame, et procede pour leur production | |
CA2948148C (fr) | Formulations d'un concentre liquide de cyclophosphamide | |
AU2006250765A1 (en) | Injectable compositions and process for preparation of such compositions | |
CA2581303A1 (fr) | Preparations contenant de la piperacilline, du tazobactam et un acide aminocarboxylique dilues dans du lactate de sodium | |
US9993464B2 (en) | Otamixaban formulations with improved stability | |
WO2017175098A1 (fr) | Formulations pharmaceutiques liquides stables de bendamustine | |
WO2022106630A1 (fr) | Formulations stables comprenant de la pipéracilline et/ou du tazobactam | |
JP3941132B2 (ja) | 抗真菌剤 | |
WO2022106611A1 (fr) | Nouvelles compositions de composés de bêta-lactame | |
PT85808B (pt) | Processo de preparacao de uma solucao aquosa contendo uma quinolona do acido carboxilico | |
JP2761005B2 (ja) | セファロスポリン含有注射用組成物 | |
AU2015200599B2 (en) | Ceftolozane Antibiotic Compositions | |
JPH02124822A (ja) | セファロスポリン含有注射用組成物 | |
JPH1025254A (ja) | 配合禁忌の防止された水溶性製剤 | |
TW202416947A (zh) | 液體達巴萬星組成物 | |
EP4134083A1 (fr) | Compositions pharmaceutiques de bortézomib | |
JPS59219211A (ja) | 液状化粧料 | |
US8044104B2 (en) | Prostaglandin derivative-containing aqueous liquid preparation | |
AU604094B2 (en) | Stable, injectable solutions of vinca dimer salts | |
JP2003063963A (ja) | オザグレルナトリウム含有注射液 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21814784 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |