CA2140701A1 - Liposome solutions - Google Patents
Liposome solutionsInfo
- Publication number
- CA2140701A1 CA2140701A1 CA002140701A CA2140701A CA2140701A1 CA 2140701 A1 CA2140701 A1 CA 2140701A1 CA 002140701 A CA002140701 A CA 002140701A CA 2140701 A CA2140701 A CA 2140701A CA 2140701 A1 CA2140701 A1 CA 2140701A1
- Authority
- CA
- Canada
- Prior art keywords
- solution according
- liposome solution
- heptane
- beta
- liposomes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000002502 liposome Substances 0.000 title claims abstract description 48
- 229940123930 Lactamase inhibitor Drugs 0.000 claims abstract description 12
- 230000003115 biocidal effect Effects 0.000 claims abstract 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 12
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical group 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 claims description 9
- 229960003865 tazobactam Drugs 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 6
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 6
- 235000012000 cholesterol Nutrition 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 5
- 229930186147 Cephalosporin Natural products 0.000 claims description 3
- 229930182555 Penicillin Natural products 0.000 claims description 3
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 claims description 3
- 229960003644 aztreonam Drugs 0.000 claims description 3
- -1 benzyloxy, amino Chemical group 0.000 claims description 3
- 229940124587 cephalosporin Drugs 0.000 claims description 3
- 150000001780 cephalosporins Chemical class 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000003381 stabilizer Substances 0.000 claims description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 2
- FKENQMMABCRJMK-LWOQYNTDSA-N (5r)-3,3-dimethyl-4,4,7-trioxo-4$l^{6}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=S1(=O)C(C)(C)C(C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-LWOQYNTDSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 claims description 2
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 claims description 2
- 229960003324 clavulanic acid Drugs 0.000 claims description 2
- 238000001727 in vivo Methods 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 229960005256 sulbactam Drugs 0.000 claims description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims 1
- 229940049954 penicillin Drugs 0.000 claims 1
- 239000000243 solution Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000013543 active substance Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- XAAQLSCBLSUACT-UHFFFAOYSA-N 1,2-diazabicyclo[3.2.0]heptane-6-sulfonic acid Chemical compound N1CCC2C(S(=O)(=O)O)CN21 XAAQLSCBLSUACT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000008344 egg yolk phospholipid Substances 0.000 description 2
- PGFHUTLGRFUELA-UHFFFAOYSA-N heptane-2-sulfonic acid Chemical compound CCCCCC(C)S(O)(=O)=O PGFHUTLGRFUELA-UHFFFAOYSA-N 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 150000002960 penicillins Chemical class 0.000 description 2
- 239000004417 polycarbonate Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VTRGDCSNDDFHIC-PWSUYJOCSA-N (1r,5s)-4-(2-anilinoacetyl)-6-oxo-4,7-diazabicyclo[3.2.0]heptane-7-sulfonic acid Chemical compound C([C@H]1N(C([C@H]11)=O)S(=O)(=O)O)CN1C(=O)CNC1=CC=CC=C1 VTRGDCSNDDFHIC-PWSUYJOCSA-N 0.000 description 1
- NQTZUGXGGNMKFH-MXWKQRLJSA-N (1r,5s)-4-[(2r)-2-amino-2-(4-hydroxyphenyl)acetyl]-6-oxo-4,7-diazabicyclo[3.2.0]heptane-7-sulfonic acid Chemical compound C1([C@H](C(=O)N2[C@H]3[C@H](N(C3=O)S(O)(=O)=O)CC2)N)=CC=C(O)C=C1 NQTZUGXGGNMKFH-MXWKQRLJSA-N 0.000 description 1
- JQLWSRMROICNBK-VDTYLAMSSA-N (1r,5s)-4-[2-(1-methyltetrazol-5-yl)sulfanylacetyl]-6-oxo-4,7-diazabicyclo[3.2.0]heptane-7-sulfonic acid Chemical compound CN1N=NN=C1SCC(=O)N1[C@H](C(=O)N2S(O)(=O)=O)[C@H]2CC1 JQLWSRMROICNBK-VDTYLAMSSA-N 0.000 description 1
- CHLHOHBQOKNRPV-PWSUYJOCSA-N (1r,5s)-4-[2-(3-aminoanilino)acetyl]-6-oxo-4,7-diazabicyclo[3.2.0]heptane-7-sulfonic acid Chemical compound NC1=CC=CC(NCC(=O)N2[C@H]3[C@H](N(C3=O)S(O)(=O)=O)CC2)=C1 CHLHOHBQOKNRPV-PWSUYJOCSA-N 0.000 description 1
- VYFKGTVIKRZQEX-PWSUYJOCSA-N (1r,5s)-4-[2-(benzotriazol-1-ylsulfanyl)acetyl]-6-oxo-4,7-diazabicyclo[3.2.0]heptane-7-sulfonic acid Chemical compound N1=NC2=CC=CC=C2N1SCC(=O)N1CC[C@H]2N(S(=O)(=O)O)C(=O)[C@H]21 VYFKGTVIKRZQEX-PWSUYJOCSA-N 0.000 description 1
- IOBPNPLVGSCZSV-ZJUUUORDSA-N (1r,5s)-6-oxo-4-(phenylcarbamoyl)-4,7-diazabicyclo[3.2.0]heptane-7-sulfonic acid Chemical compound C([C@H]1N(C([C@H]11)=O)S(=O)(=O)O)CN1C(=O)NC1=CC=CC=C1 IOBPNPLVGSCZSV-ZJUUUORDSA-N 0.000 description 1
- AKDVJJIQPOJOMC-UHFFFAOYSA-N 4,4,7-trioxo-4$l^{6}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound OC(=O)C1CS(=O)(=O)C2CC(=O)N12 AKDVJJIQPOJOMC-UHFFFAOYSA-N 0.000 description 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 1
- CZNJCCVKDVCRKF-UHFFFAOYSA-N Benzyl sulfate Chemical compound OS(=O)(=O)OCC1=CC=CC=C1 CZNJCCVKDVCRKF-UHFFFAOYSA-N 0.000 description 1
- UGCXDQHCDHSXBU-ZCSKGCSWSA-N C(/[C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(=O)OC(C=1C=CC=CC=1)C=1C=CC=CC=1)(=O)=O)=C\C(=O)OCC1=CC=CC=C1 Chemical compound C(/[C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(=O)OC(C=1C=CC=CC=1)C=1C=CC=CC=1)(=O)=O)=C\C(=O)OCC1=CC=CC=C1 UGCXDQHCDHSXBU-ZCSKGCSWSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- HDSDLICLANUNBY-PNMNSLMXSA-M [Na+].O=S1(=O)[C@@](C)(\C=C/C(N)=O)[C@H](C([O-])=O)N2C(=O)C[C@H]21 Chemical compound [Na+].O=S1(=O)[C@@](C)(\C=C/C(N)=O)[C@H](C([O-])=O)N2C(=O)C[C@H]21 HDSDLICLANUNBY-PNMNSLMXSA-M 0.000 description 1
- HDSDLICLANUNBY-LSTOSFGNSA-M [Na+].O=S1(=O)[C@@](C)(\C=C\C(N)=O)[C@H](C([O-])=O)N2C(=O)C[C@H]21 Chemical compound [Na+].O=S1(=O)[C@@](C)(\C=C\C(N)=O)[C@H](C([O-])=O)N2C(=O)C[C@H]21 HDSDLICLANUNBY-LSTOSFGNSA-M 0.000 description 1
- GSQXUHOIXPEZOL-RQLHMRLNSA-M [Na+].O=S1(=O)[C@](/C=C/C(=O)OCC)(C)[C@H](C([O-])=O)N2C(=O)C[C@H]21 Chemical compound [Na+].O=S1(=O)[C@](/C=C/C(=O)OCC)(C)[C@H](C([O-])=O)N2C(=O)C[C@H]21 GSQXUHOIXPEZOL-RQLHMRLNSA-M 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- XMQVYNAURODYCQ-SLFBBCNNSA-N apalcillin Chemical compound C1([C@@H](NC(=O)C=2C(=C3N=CC=CC3=NC=2)O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 XMQVYNAURODYCQ-SLFBBCNNSA-N 0.000 description 1
- 229950001979 apalcillin Drugs 0.000 description 1
- OQJDOGSVJMFFFU-XTSCALQBSA-N benzhydryl (2s,3s,5r)-3-[(e)-3-amino-3-oxoprop-1-enyl]-3-methyl-4,4,7-trioxo-4$l^{6}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound O=C([C@H]1[C@@](S([C@H]2N1C(C2)=O)(=O)=O)(\C=C\C(N)=O)C)OC(C=1C=CC=CC=1)C1=CC=CC=C1 OQJDOGSVJMFFFU-XTSCALQBSA-N 0.000 description 1
- CBKBSXNWEVPYMG-CHESKEECSA-N benzhydryl (2s,3s,5r)-3-[(e)-3-ethoxy-3-oxoprop-1-enyl]-3-methyl-4,4,7-trioxo-4$l^{6}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound O=C([C@H]1[C@](S([C@H]2N1C(C2)=O)(=O)=O)(C)/C=C/C(=O)OCC)OC(C=1C=CC=CC=1)C1=CC=CC=C1 CBKBSXNWEVPYMG-CHESKEECSA-N 0.000 description 1
- LOHGIPNFTZQTSY-CHESKEECSA-N benzhydryl (2s,3s,5r)-3-[(e)-3-ethoxy-3-oxoprop-1-enyl]-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound O=C([C@@H]1N2C(=O)C[C@H]2S[C@@]1(C)/C=C/C(=O)OCC)OC(C=1C=CC=CC=1)C1=CC=CC=C1 LOHGIPNFTZQTSY-CHESKEECSA-N 0.000 description 1
- FBMGFBJIQUKPAK-FRBBGPADSA-N benzhydryl (2s,3s,5r)-3-[(z)-2-cyanoethenyl]-3-methyl-4,4,7-trioxo-4$l^{6}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound O=C([C@H]1[C@@](S([C@H]2N1C(C2)=O)(=O)=O)(\C=C/C#N)C)OC(C=1C=CC=CC=1)C1=CC=CC=C1 FBMGFBJIQUKPAK-FRBBGPADSA-N 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- BDNDVGIJKCOILH-UHFFFAOYSA-N bicyclo[3.2.0]heptane-6-sulfonic acid Chemical compound C1CCC2C(S(=O)(=O)O)CC21 BDNDVGIJKCOILH-UHFFFAOYSA-N 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- 229960004755 ceftriaxone Drugs 0.000 description 1
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 229960002182 imipenem Drugs 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 229960002260 meropenem Drugs 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- OWKLEMZTTMIWQV-UHFFFAOYSA-N methyl 4,4,7-trioxo-4lambda6-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound COC(=O)C1N2C(CC2S(C1)(=O)=O)=O OWKLEMZTTMIWQV-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- 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 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- DRNHQKOSAXWVCX-LSTOSFGNSA-M sodium;(2s,3s,5r)-3-[(e)-2-cyanoethenyl]-3-methyl-4,4,7-trioxo-4$l^{6}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [Na+].O=S1(=O)[C@@](C)(\C=C\C#N)[C@H](C([O-])=O)N2C(=O)C[C@H]21 DRNHQKOSAXWVCX-LSTOSFGNSA-M 0.000 description 1
- DRNHQKOSAXWVCX-PNMNSLMXSA-M sodium;(2s,3s,5r)-3-[(z)-2-cyanoethenyl]-3-methyl-4,4,7-trioxo-4$l^{6}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [Na+].O=S1(=O)[C@@](C)(\C=C/C#N)[C@H](C([O-])=O)N2C(=O)C[C@H]21 DRNHQKOSAXWVCX-PNMNSLMXSA-M 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
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Abstract
The invention is concerned with aqueous liposome solutions which contain a .beta.-lactamase inhibitor and, if desired, a .beta.-lactam antibiotic.
Description
- ` ~14070~
The present invention is concerned with aqueous liposome 5 solutions which contain a ~-lactamase inhibitor.
It has been found that the residence time of ~-lactamase inhibitors, such as tazobactam, in the body is increased when the ~-lactamase inhibitor is administered in the form of an aqueous 10 liposome solution. Furthermore, it has been found that the resid-ence time in the plasma of the ~-lactamase inhibitor administ-ered in such a form can be influenced by the size of the liposomes.
The liposomes of the compositions in accordance with the invention can be composed of substances which are known as liposome formers. Preferably, the liposomes consist of phosphatidylcholine, such as egg lecithin or soya lecithin, and phosphatidylglycerol and, if desired, cholesterol. The phosph-20 atidylcholine:phosphatidylglycerol molar ratio is conveniently 10:0-1, preferably 10:1. The phosphatidylcholine:cholesterol molar ratio is conveniently 10:0-5, preferably 10:5. The concentration of the liposome former (i.e. phosphatidylcholine, phosphatidylglycerol and cholesterol) in the liposome solution is 2 5 conveniently about 10-400 mg/ml, preferably about 100-250 mg/ml.
The term N,~-lactamase inhibitor" denotes substances which inhibit the enzymatic cleavage of the ,~-lactam ring of ~-lactam 3 0 antibiotics, such as penicillins, cephalosporins, monolactams and carbapenems. Tazobactam, sulbactam and clavulanic acid are examples of ,B-lactamase inhibitors. Examples of other ,B-lactam-ase inhibitors are the compounds described in European Patent Publication A-0 508 234, especially the compounds benzyl (1 S,5R)-7-oxo-6-sulpho-2,6-diazabicyclo[3.2.0]-heptane-2-carboxylate, (1 S,5R)-2-[(Z)-3-a-acetamidocinnamoyl]-7-oxo-2,6-Grn/So 21.11.94 diazabicyclo[3.2.0]heptane-6-sulphonic acid, (R/S)-a-(1 S,5R)-2-[2-carboxy-2-(3-thienyl)acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid, (1 S,5R)-7-oxo-2-(3-pyridylacetyl)-2,6-diazabicyclo[3.2.0]-5 heptane-6-sulphonic acid, (1 S,5R)-2-[(R,S)-2-indolylcarbonyl]-7-oxo-2,6-diaza-bicyclo[3.2.0]heptane-6-sulphonic acid, (1 S,5R)-2-[(R)-a-hydroxyphenylacetyl]-7-oxo-2,6-diaza-bicyclo[3.2.0]heptane-6-sulphonic acid, 1 0(1 S,5R)-2-[(S)-a-hydroxyphenylacetyl]-7-oxo-2,6-diaza-bicyclo[3.2.0]heptane-6-sulphonic acid, R(a)-[[(1 S,5R)-7-oxo-6-sulpho-2,6-diazabicyclo[3.2.0]hept-2-yl]carbonyl]benzyl sulphate, (1 S,5R)-2-(2-amino-4-thiazoleglyoxyloyl)-7-oxo-2,6-15 diazabicyclo[3.2.0]heptane-6-sulphonic acid (1 S,5R)-7-oxo-2-(D-2-phenylglycyl)-6-sulpho-2,6-diaza-bicyclo[3.2.0]heptane-6-sulphonic acid, (1 S,5R)-7-oxo-2-(L-2-phenylglycyl)-6-sulpho-2,6-diaza-bicyclo[3.2.0]heptane-6-sulphonic acid, 20(1 S,5R)-7-oxo-2-L-tyrosyl-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid, (1 S,5R)-2-[D-2-(p-hydroxyphenyl)glycyl]-7-oxo-2,6-diaza-bicyclo[3.2.0]-heptane-6-sulphonic acid, (1 S,5R)-7-oxo-2-L-tryptophanyl-2,6-diazabicyclo]3.2.0]-2 5 heptane-6-sulphonic acid, (1 S,5R)-2-[(R or S)-a-amino-(2-thienyl)acetyl]-7-oxo-2,6-diazabicyclo-[3.2.0]heptane-6-sulphonic acid (1 S,5R)-7-oxo-2-(phenylcarbamoyl)-6-sulpho-2,6-diaza-bicyclo[3.2.0]heptane, 3 0(1 S,5R)-2-(benzylcarbamoyl)-7-oxo-6-sulpho-2,6-diaza-bicyclo[3.2.0]heptane, (1 S,5R)-7-oxo-2-(N-phenylglycyl)-2,6-diazabicyclo[3.2.0]-heptane-6-sulphonic acid, (1 S,5R)-2-[(E)-3-(2-furyl)acryloyl]-7-oxo-2,6-diaza-3 5 bicyclo[3.2.0]heptane-6-sulphonic acid, (1 S,5R)-2-[N-(m-aminophenyl)glycyl]-7-oxo-2,6-diaza-bicyclo[3.2.0]-heptane-6-sulphonic acid, (1 S,5R)-2-[[(1 -methyl-1 H-tetrazol-5-yl)thio]acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid, (1 S,5R)-2-[[(1 H-benzotriazol-1 -yl)thio]acetyl]-7-oxo-2,6-diazabicyclo-[3.2.0]heptane-6-sulphonic acid and (1 S,5R)-2-[(E)-3-(3-indolyl)acryloyl]-7-oxo-2,6-diaza-5 bicyclo]3.2.0]heptane-6-sulphonic acid, as well as pharmaceutically compatible salts of these compounds.
Further ~-lactamase inhibitors which can be present in the liposome solutions in accordance with the invention are the 10 compounds of general formula l ()n CooR3 wherein one of R1 and R2 signifies -COR4, -CN, -CH2OR5 or -SO2R6 and the other signifies H, -COR4, -CN, -CH2OR5 or -SO2R6 or lower alkyl;
R3 = H, lower alkyl, aryl-alkyl, allyl or a residue which is cleavable in vivo;
R4 = H, lower alkyl, lower alkoxy, benzyloxy, amino or lower alkylamino;
R5 = H or-CONH2;
R6 = lower alkyl and n = 0, 1 or 2 as well as the pharmaceutically compatible salts of these 25 compounds, especially the compounds benzhydryl (E/Z)-(2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-7-oxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, benzhydryl (E)-(2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-30 4,4,7-trioxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate, benzhydryl (Z)-(2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, sodium (E)-(2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3 .2.0]heptane-2-carboxylate, ~140~U~
sodium (Z)-(2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3 .2.0]heptane-2-carboxylate, benzhydryl (E/Z)-(2S,3S,5R)-3-(2-carbamoyl-vinyl)-3-methyl-7-oxo-4-thia-1 -aza-bicyclo[3 .2.0]heptane-2-carboxylate, benzhydryl (E)-(2S,3S,5R)-3-(2-carbamoyl-vinyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3 .2.0]heptane-2-carboxylate, benzhydryl (Z)-(2S,3S,5R)-3-(2-carbamoyl-vinyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-1 0 carboxylate, sodium (E)-(2S,3S,5R)-3-(2-carbamoyl-vinyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, sodium (Z)-(2S,3S,5R)-3-(2-carbamoyl-vinyl)-3-methyl-4,4 ,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, benzhydryl (E)-(2S,3S,5R)-3-(2-ethoxycarbonyl-vinyl)-3-methyl-7-oxo-4-thia-1 -aza-bicyclo[3 .2.0]heptane-2-carboxylate, benzhydryl (E)-(2S,3S,5R)-3-(2-ethoxycarbonyl-vinyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, sodium (E)-(2S,3S,5R)-3-(2-ethoxycarbonyl-vinyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, benzhydryl (E)-(2S,3S,5R)-3-(2-benzyloxycarbonyl-vinyl)-3-methyl-7-oxo-4-thia-1 -aza-bicyclo[3 .2.0]heptane-2- 5 carboxylate, benzhydryl (E)-(2S,3S,5R)-3-(2-benzyloxycarbonyl-vinyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, and sodium (E)-(2S,3S,5R)-3-(2-benzyloxycarbonyl-vinyl)-3-30 methyl-4,4,7-trioxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate.
The concentration of the ~-lactamase inhibitor in the liposomes depends on the specific ,~-lactamase inhibitor and must 35 be determined on a case by case basis. Too high active substance concentrations can lead, after administration of the liposomes, to rupture of the liposomes (osmotic effect) in the bloodstream or in the tissue. For example, the tazobactam concentration in the 21~070~
liposomes is conveniently not more than 0.2 mg/mg liposome former and is preferably about 0.1 to 0.15 mgtmg liposome former.
It has been found that the size of the liposomes influences the residence time (i.e. the half-life) of the ,B-lactamase inhibitor in plasma. In order to achieve a long residence time the diameter of the liposomes should be smaller than about 250 nm. Lipo-somes having a diameter of about 100-200 nm, especially about 10 150 nm, are preferred in accordance with the invention.
The liposome solutions in accordance with the invention can be administered parenterally, e.g. intravenously, intramuscularly or subcutaneously, taking into consideration the administration 15 guidelines known for the active substance contained therein.
They can contain adjuvants which are usually used in pharma-ceutical liposome solutions for parenteral administration, especially stabilizers such as a sugar, e.g. sucrose or trehalose, as well as agents for adjusting the pH and the osmotic pressure.
20 Furthermore, the liposome solutions in accordance with the invention can contain ,~-lactam antibiotics, especially penicillins or cephalosporins, e.g. piperacillin or apalcillin; or such as e.g.
ceftriaxone, ceftazid or cefoperazone; or a carbapenem, such as imipenem or meropenem; or a monobactam, such as aztreonam.
25 Further, they can be present in Iyophilized form.
The liposome solutions in accordance with the invention can be manufactured in a manner known per se, for example by preparing a solvent-free film from the liposome formers using a 3 0 suitable solvent, e.g. chloroform/methanol, hydrating this film with an aqueous solution of the ,~-lactamase inhibitor and converting the thus-obtained multilamellar vesicle into liposomes of the desired dimension by extrusion.
3 5 The following Examples illustrate the invention.
21gO70~
Fxample 1 50 mg of a mixture of egg lecithin (Lipoid E PC, Lipoid KG, Ludwigshafen, Germany), phosphatidylglycerol (Lipoid PG, 5 16:0/16:0, Lipoid KG, Ludwigshafen, Germany) and cholesterol in the molar ratio of 10:1:5 were dissolved in chloroform/methanol (1:1 parts by vol.) in a round flask. The solvent was removed in a rotating flask at 40C under reduced pressure (finally at 0.01 mbar). The residual film was treated with 1 ml of a 10% aqueous 10 solution of tazobactam Na and hydrated by treatment in a vortex mixer. The thus-obtained multilamellar tazobactam-containing vesicles were pressed three times under nitrogen pressure (6-8 bar) through a 0.2 ~lm and once or twice through a 0.1 ~lm polycarbonate filter (Nucleopore, Pleasanton, CA., USA). The 15 thus-obtained liposomes had an average diameter of 150nm (measured by quasi-elastic light scattering with a Nano-Sizer PSM 78, Coulter Electronics, Krefeld, Germany). Liposomes having a larger or smaller diameter can be manufactured analogously by choosing a filter of larger (e.g. 0.4 llm) or smaller (e.g. 0.05 ~m) 20 pore size.
Fxam~le ~
Tazobactam liposomes (1 ml/kg, 5.8-10.4 mg tazobactam/
25 kg) of various sizes were injected into male albino rats through a jugular vein catheter. After rinsing the catheter with physio-logical saline plasma samples were removed through the catheter at various intervals, with the plasma withdrawn being replaced by saline solution. The tazobactam concentration in the samples 30 was determined by HPLC. The results are reproduced hereinafter:
Formulation Liposome t 1/2 AUC
diameter [h] [mg.h/ml]
[nm]
Liposomes 146 5.0i1.9 456.3i250.1 Liposomes 236 1.4+0.3 135.1i 62.5 Aqueous solution 0.14 5.27 21~0701 The above results show that by administration in the form of a liposome solution the residence time of the active substance in plasma was increased and that this effect was stronger in the 5 case of solutions with smaller liposomes than with larger liposomes.
The present invention is concerned with aqueous liposome 5 solutions which contain a ~-lactamase inhibitor.
It has been found that the residence time of ~-lactamase inhibitors, such as tazobactam, in the body is increased when the ~-lactamase inhibitor is administered in the form of an aqueous 10 liposome solution. Furthermore, it has been found that the resid-ence time in the plasma of the ~-lactamase inhibitor administ-ered in such a form can be influenced by the size of the liposomes.
The liposomes of the compositions in accordance with the invention can be composed of substances which are known as liposome formers. Preferably, the liposomes consist of phosphatidylcholine, such as egg lecithin or soya lecithin, and phosphatidylglycerol and, if desired, cholesterol. The phosph-20 atidylcholine:phosphatidylglycerol molar ratio is conveniently 10:0-1, preferably 10:1. The phosphatidylcholine:cholesterol molar ratio is conveniently 10:0-5, preferably 10:5. The concentration of the liposome former (i.e. phosphatidylcholine, phosphatidylglycerol and cholesterol) in the liposome solution is 2 5 conveniently about 10-400 mg/ml, preferably about 100-250 mg/ml.
The term N,~-lactamase inhibitor" denotes substances which inhibit the enzymatic cleavage of the ,~-lactam ring of ~-lactam 3 0 antibiotics, such as penicillins, cephalosporins, monolactams and carbapenems. Tazobactam, sulbactam and clavulanic acid are examples of ,B-lactamase inhibitors. Examples of other ,B-lactam-ase inhibitors are the compounds described in European Patent Publication A-0 508 234, especially the compounds benzyl (1 S,5R)-7-oxo-6-sulpho-2,6-diazabicyclo[3.2.0]-heptane-2-carboxylate, (1 S,5R)-2-[(Z)-3-a-acetamidocinnamoyl]-7-oxo-2,6-Grn/So 21.11.94 diazabicyclo[3.2.0]heptane-6-sulphonic acid, (R/S)-a-(1 S,5R)-2-[2-carboxy-2-(3-thienyl)acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid, (1 S,5R)-7-oxo-2-(3-pyridylacetyl)-2,6-diazabicyclo[3.2.0]-5 heptane-6-sulphonic acid, (1 S,5R)-2-[(R,S)-2-indolylcarbonyl]-7-oxo-2,6-diaza-bicyclo[3.2.0]heptane-6-sulphonic acid, (1 S,5R)-2-[(R)-a-hydroxyphenylacetyl]-7-oxo-2,6-diaza-bicyclo[3.2.0]heptane-6-sulphonic acid, 1 0(1 S,5R)-2-[(S)-a-hydroxyphenylacetyl]-7-oxo-2,6-diaza-bicyclo[3.2.0]heptane-6-sulphonic acid, R(a)-[[(1 S,5R)-7-oxo-6-sulpho-2,6-diazabicyclo[3.2.0]hept-2-yl]carbonyl]benzyl sulphate, (1 S,5R)-2-(2-amino-4-thiazoleglyoxyloyl)-7-oxo-2,6-15 diazabicyclo[3.2.0]heptane-6-sulphonic acid (1 S,5R)-7-oxo-2-(D-2-phenylglycyl)-6-sulpho-2,6-diaza-bicyclo[3.2.0]heptane-6-sulphonic acid, (1 S,5R)-7-oxo-2-(L-2-phenylglycyl)-6-sulpho-2,6-diaza-bicyclo[3.2.0]heptane-6-sulphonic acid, 20(1 S,5R)-7-oxo-2-L-tyrosyl-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid, (1 S,5R)-2-[D-2-(p-hydroxyphenyl)glycyl]-7-oxo-2,6-diaza-bicyclo[3.2.0]-heptane-6-sulphonic acid, (1 S,5R)-7-oxo-2-L-tryptophanyl-2,6-diazabicyclo]3.2.0]-2 5 heptane-6-sulphonic acid, (1 S,5R)-2-[(R or S)-a-amino-(2-thienyl)acetyl]-7-oxo-2,6-diazabicyclo-[3.2.0]heptane-6-sulphonic acid (1 S,5R)-7-oxo-2-(phenylcarbamoyl)-6-sulpho-2,6-diaza-bicyclo[3.2.0]heptane, 3 0(1 S,5R)-2-(benzylcarbamoyl)-7-oxo-6-sulpho-2,6-diaza-bicyclo[3.2.0]heptane, (1 S,5R)-7-oxo-2-(N-phenylglycyl)-2,6-diazabicyclo[3.2.0]-heptane-6-sulphonic acid, (1 S,5R)-2-[(E)-3-(2-furyl)acryloyl]-7-oxo-2,6-diaza-3 5 bicyclo[3.2.0]heptane-6-sulphonic acid, (1 S,5R)-2-[N-(m-aminophenyl)glycyl]-7-oxo-2,6-diaza-bicyclo[3.2.0]-heptane-6-sulphonic acid, (1 S,5R)-2-[[(1 -methyl-1 H-tetrazol-5-yl)thio]acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid, (1 S,5R)-2-[[(1 H-benzotriazol-1 -yl)thio]acetyl]-7-oxo-2,6-diazabicyclo-[3.2.0]heptane-6-sulphonic acid and (1 S,5R)-2-[(E)-3-(3-indolyl)acryloyl]-7-oxo-2,6-diaza-5 bicyclo]3.2.0]heptane-6-sulphonic acid, as well as pharmaceutically compatible salts of these compounds.
Further ~-lactamase inhibitors which can be present in the liposome solutions in accordance with the invention are the 10 compounds of general formula l ()n CooR3 wherein one of R1 and R2 signifies -COR4, -CN, -CH2OR5 or -SO2R6 and the other signifies H, -COR4, -CN, -CH2OR5 or -SO2R6 or lower alkyl;
R3 = H, lower alkyl, aryl-alkyl, allyl or a residue which is cleavable in vivo;
R4 = H, lower alkyl, lower alkoxy, benzyloxy, amino or lower alkylamino;
R5 = H or-CONH2;
R6 = lower alkyl and n = 0, 1 or 2 as well as the pharmaceutically compatible salts of these 25 compounds, especially the compounds benzhydryl (E/Z)-(2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-7-oxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, benzhydryl (E)-(2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-30 4,4,7-trioxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate, benzhydryl (Z)-(2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, sodium (E)-(2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3 .2.0]heptane-2-carboxylate, ~140~U~
sodium (Z)-(2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3 .2.0]heptane-2-carboxylate, benzhydryl (E/Z)-(2S,3S,5R)-3-(2-carbamoyl-vinyl)-3-methyl-7-oxo-4-thia-1 -aza-bicyclo[3 .2.0]heptane-2-carboxylate, benzhydryl (E)-(2S,3S,5R)-3-(2-carbamoyl-vinyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3 .2.0]heptane-2-carboxylate, benzhydryl (Z)-(2S,3S,5R)-3-(2-carbamoyl-vinyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-1 0 carboxylate, sodium (E)-(2S,3S,5R)-3-(2-carbamoyl-vinyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, sodium (Z)-(2S,3S,5R)-3-(2-carbamoyl-vinyl)-3-methyl-4,4 ,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, benzhydryl (E)-(2S,3S,5R)-3-(2-ethoxycarbonyl-vinyl)-3-methyl-7-oxo-4-thia-1 -aza-bicyclo[3 .2.0]heptane-2-carboxylate, benzhydryl (E)-(2S,3S,5R)-3-(2-ethoxycarbonyl-vinyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, sodium (E)-(2S,3S,5R)-3-(2-ethoxycarbonyl-vinyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, benzhydryl (E)-(2S,3S,5R)-3-(2-benzyloxycarbonyl-vinyl)-3-methyl-7-oxo-4-thia-1 -aza-bicyclo[3 .2.0]heptane-2- 5 carboxylate, benzhydryl (E)-(2S,3S,5R)-3-(2-benzyloxycarbonyl-vinyl)-3-methyl-4,4,7-trioxo-4-thia-1 -aza-bicyclo[3.2.0]heptane-2-carboxylate, and sodium (E)-(2S,3S,5R)-3-(2-benzyloxycarbonyl-vinyl)-3-30 methyl-4,4,7-trioxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate.
The concentration of the ~-lactamase inhibitor in the liposomes depends on the specific ,~-lactamase inhibitor and must 35 be determined on a case by case basis. Too high active substance concentrations can lead, after administration of the liposomes, to rupture of the liposomes (osmotic effect) in the bloodstream or in the tissue. For example, the tazobactam concentration in the 21~070~
liposomes is conveniently not more than 0.2 mg/mg liposome former and is preferably about 0.1 to 0.15 mgtmg liposome former.
It has been found that the size of the liposomes influences the residence time (i.e. the half-life) of the ,B-lactamase inhibitor in plasma. In order to achieve a long residence time the diameter of the liposomes should be smaller than about 250 nm. Lipo-somes having a diameter of about 100-200 nm, especially about 10 150 nm, are preferred in accordance with the invention.
The liposome solutions in accordance with the invention can be administered parenterally, e.g. intravenously, intramuscularly or subcutaneously, taking into consideration the administration 15 guidelines known for the active substance contained therein.
They can contain adjuvants which are usually used in pharma-ceutical liposome solutions for parenteral administration, especially stabilizers such as a sugar, e.g. sucrose or trehalose, as well as agents for adjusting the pH and the osmotic pressure.
20 Furthermore, the liposome solutions in accordance with the invention can contain ,~-lactam antibiotics, especially penicillins or cephalosporins, e.g. piperacillin or apalcillin; or such as e.g.
ceftriaxone, ceftazid or cefoperazone; or a carbapenem, such as imipenem or meropenem; or a monobactam, such as aztreonam.
25 Further, they can be present in Iyophilized form.
The liposome solutions in accordance with the invention can be manufactured in a manner known per se, for example by preparing a solvent-free film from the liposome formers using a 3 0 suitable solvent, e.g. chloroform/methanol, hydrating this film with an aqueous solution of the ,~-lactamase inhibitor and converting the thus-obtained multilamellar vesicle into liposomes of the desired dimension by extrusion.
3 5 The following Examples illustrate the invention.
21gO70~
Fxample 1 50 mg of a mixture of egg lecithin (Lipoid E PC, Lipoid KG, Ludwigshafen, Germany), phosphatidylglycerol (Lipoid PG, 5 16:0/16:0, Lipoid KG, Ludwigshafen, Germany) and cholesterol in the molar ratio of 10:1:5 were dissolved in chloroform/methanol (1:1 parts by vol.) in a round flask. The solvent was removed in a rotating flask at 40C under reduced pressure (finally at 0.01 mbar). The residual film was treated with 1 ml of a 10% aqueous 10 solution of tazobactam Na and hydrated by treatment in a vortex mixer. The thus-obtained multilamellar tazobactam-containing vesicles were pressed three times under nitrogen pressure (6-8 bar) through a 0.2 ~lm and once or twice through a 0.1 ~lm polycarbonate filter (Nucleopore, Pleasanton, CA., USA). The 15 thus-obtained liposomes had an average diameter of 150nm (measured by quasi-elastic light scattering with a Nano-Sizer PSM 78, Coulter Electronics, Krefeld, Germany). Liposomes having a larger or smaller diameter can be manufactured analogously by choosing a filter of larger (e.g. 0.4 llm) or smaller (e.g. 0.05 ~m) 20 pore size.
Fxam~le ~
Tazobactam liposomes (1 ml/kg, 5.8-10.4 mg tazobactam/
25 kg) of various sizes were injected into male albino rats through a jugular vein catheter. After rinsing the catheter with physio-logical saline plasma samples were removed through the catheter at various intervals, with the plasma withdrawn being replaced by saline solution. The tazobactam concentration in the samples 30 was determined by HPLC. The results are reproduced hereinafter:
Formulation Liposome t 1/2 AUC
diameter [h] [mg.h/ml]
[nm]
Liposomes 146 5.0i1.9 456.3i250.1 Liposomes 236 1.4+0.3 135.1i 62.5 Aqueous solution 0.14 5.27 21~0701 The above results show that by administration in the form of a liposome solution the residence time of the active substance in plasma was increased and that this effect was stronger in the 5 case of solutions with smaller liposomes than with larger liposomes.
Claims (11)
1. An aqueous liposome solution containing a .beta.-lactam-ase inhibitor and, if desired, a stabilizer.
2. A liposome solution according to Claim 1, wherein the .beta.-lactamase inhibitor is tazobactam, sulbactam or clavulanic acid; or a .beta.-lactamase inhibitor described in European Patent Publication A-0 508 234; or a compound of the general formula I
wherein one of R1 and R2 signifies -COR4, -CN, -CH2OR5 or -SO2R6 and the other signifies H, -COR4, -CN, -CH2OR5 or -SO2R6 or lower alkyl;
R3 = H, lower alkyl, aryl-alkyl, allyl or a residue which is cleavable in vivo;
R4 = H, lower alkyl, lower alkoxy, benzyloxy, amino or lower alkylamino;
R5 = H or-CONH2;
R6 = lower alkyl and n = 0, 1 or 2 or a pharmaceutically compatible salt thereof.
wherein one of R1 and R2 signifies -COR4, -CN, -CH2OR5 or -SO2R6 and the other signifies H, -COR4, -CN, -CH2OR5 or -SO2R6 or lower alkyl;
R3 = H, lower alkyl, aryl-alkyl, allyl or a residue which is cleavable in vivo;
R4 = H, lower alkyl, lower alkoxy, benzyloxy, amino or lower alkylamino;
R5 = H or-CONH2;
R6 = lower alkyl and n = 0, 1 or 2 or a pharmaceutically compatible salt thereof.
3. A liposome solution according to claim 1 or 2, where-in the stabilizer is a sugar, such as sucrose or trehalose.
4. A liposome solution according to claims 1-3, wherein the liposomes consist of phosphatidylcholine and phosphatidyl-glycerol and, if desired, cholesterol.
5. A liposome solution according to claim 4, wherein the molar ratio of phosphatidylcholine, phosphatidylglycerol and cholesterol is 10:0-1:0-5.
6. A liposome solution according to claims 1-5, wherein the liposomes have an average diameter of 50-250 nm.
7. A liposome solution according to claim 6, wherein the liposomes have an average diameter of about 150 nm.
8. A liposome solution according to claims 1-7, wherein a .beta.-lactam antibiotic is also present.
9. A lyophilized liposome preparation according to claims 1-8.
10. A liposome solution according to claims 1-9, wherein the .beta.-lactam antibiotic is a penicillin, cephalosporin, carbapenem or monobactam.
11. The invention as described hereinbefore, especially with reference to the Examples.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH21394 | 1994-01-25 | ||
| CH213/94 | 1994-01-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2140701A1 true CA2140701A1 (en) | 1995-07-26 |
Family
ID=4181848
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002140701A Abandoned CA2140701A1 (en) | 1994-01-25 | 1995-01-20 | Liposome solutions |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0664117A1 (en) |
| JP (1) | JPH07206713A (en) |
| KR (1) | KR950031041A (en) |
| CN (1) | CN1111125A (en) |
| AU (1) | AU699142B2 (en) |
| BR (1) | BR9500296A (en) |
| CA (1) | CA2140701A1 (en) |
| NZ (1) | NZ270362A (en) |
| RU (1) | RU95101041A (en) |
| ZA (1) | ZA95404B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8476425B1 (en) | 2012-09-27 | 2013-07-02 | Cubist Pharmaceuticals, Inc. | Tazobactam arginine compositions |
| US8809314B1 (en) | 2012-09-07 | 2014-08-19 | Cubist Pharmacueticals, Inc. | Cephalosporin compound |
| US8906898B1 (en) | 2013-09-27 | 2014-12-09 | Calixa Therapeutics, Inc. | Solid forms of ceftolozane |
| US8968753B2 (en) | 2013-03-15 | 2015-03-03 | Calixa Therapeutics, Inc. | Ceftolozane-tazobactam pharmaceutical compositions |
| US9044485B2 (en) | 2013-03-15 | 2015-06-02 | Calixa Therapeutics, Inc. | Ceftolozane antibiotic compositions |
| US9872906B2 (en) | 2013-03-15 | 2018-01-23 | Merck Sharp & Dohme Corp. | Ceftolozane antibiotic compositions |
| US10376496B2 (en) | 2013-09-09 | 2019-08-13 | Merck, Sharp & Dohme Corp. | Treating infections with ceftolozane/tazobactam in subjects having impaired renal function |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9616536D0 (en) * | 1996-08-06 | 1996-09-25 | Quadrant Holdings Cambridge | Co-amoxiclav dosage form |
| US7378408B2 (en) * | 2001-11-30 | 2008-05-27 | Pfizer Inc. | Methods of treatment and formulations of cephalosporin |
| CN102048740B (en) * | 2010-12-02 | 2012-06-13 | 郝志艳 | Liposome injection prepared from ceftriaxone sodium tazobactam sodium medicinal composition |
| EP3616695A1 (en) | 2011-09-09 | 2020-03-04 | Merck Sharp & Dohme Corp. | Methods for treating intrapulmonary infections |
| CN102973568B (en) * | 2012-12-10 | 2014-08-27 | 江苏开元医药化工有限公司 | Preparation method of liposome of medicine composition of ceftriaxone sodium and sulbactam sodium |
| CN112791074B (en) * | 2021-03-17 | 2022-10-04 | 中山大学 | Application of houttuynin and/or sodium new houttuynin in preparing NDM-1 inhibitor |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1237671A (en) * | 1983-08-01 | 1988-06-07 | Michael W. Fountain | Enhancement of pharmaceutical activity |
| IE58981B1 (en) * | 1985-10-15 | 1993-12-15 | Vestar Inc | Anthracycline antineoplastic agents encapsulated in phospholipid micellular particles |
| EP0479582A1 (en) * | 1990-10-03 | 1992-04-08 | Alexander Karl Friedrich Wilhelm Overweg | Restorative periodontal technique |
-
1995
- 1995-01-11 EP EP95100293A patent/EP0664117A1/en not_active Withdrawn
- 1995-01-18 ZA ZA95404A patent/ZA95404B/en unknown
- 1995-01-19 NZ NZ270362A patent/NZ270362A/en unknown
- 1995-01-19 AU AU10298/95A patent/AU699142B2/en not_active Ceased
- 1995-01-20 CA CA002140701A patent/CA2140701A1/en not_active Abandoned
- 1995-01-23 CN CN95101683A patent/CN1111125A/en active Pending
- 1995-01-23 RU RU95101041/14A patent/RU95101041A/en unknown
- 1995-01-24 JP JP7008940A patent/JPH07206713A/en active Pending
- 1995-01-24 KR KR1019950001129A patent/KR950031041A/en not_active Application Discontinuation
- 1995-01-24 BR BR9500296A patent/BR9500296A/en not_active Application Discontinuation
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8809314B1 (en) | 2012-09-07 | 2014-08-19 | Cubist Pharmacueticals, Inc. | Cephalosporin compound |
| US8685957B1 (en) | 2012-09-27 | 2014-04-01 | Cubist Pharmaceuticals, Inc. | Tazobactam arginine compositions |
| US8476425B1 (en) | 2012-09-27 | 2013-07-02 | Cubist Pharmaceuticals, Inc. | Tazobactam arginine compositions |
| US10420841B2 (en) | 2013-03-15 | 2019-09-24 | Merck, Sharp & Dohme Corp. | Ceftolozane antibiotic compositions |
| US11278622B2 (en) | 2013-03-15 | 2022-03-22 | Merck Sharp & Dohme Corp. | Ceftolozane antibiotic compositions |
| US8968753B2 (en) | 2013-03-15 | 2015-03-03 | Calixa Therapeutics, Inc. | Ceftolozane-tazobactam pharmaceutical compositions |
| US9044485B2 (en) | 2013-03-15 | 2015-06-02 | Calixa Therapeutics, Inc. | Ceftolozane antibiotic compositions |
| US9320740B2 (en) | 2013-03-15 | 2016-04-26 | Merck Sharp & Dohme Corp. | Ceftolozane-tazobactam pharmaceutical compositions |
| US9872906B2 (en) | 2013-03-15 | 2018-01-23 | Merck Sharp & Dohme Corp. | Ceftolozane antibiotic compositions |
| US9925196B2 (en) | 2013-03-15 | 2018-03-27 | Merck Sharp & Dohme Corp. | Ceftolozane-tazobactam pharmaceutical compositions |
| US10376496B2 (en) | 2013-09-09 | 2019-08-13 | Merck, Sharp & Dohme Corp. | Treating infections with ceftolozane/tazobactam in subjects having impaired renal function |
| US10933053B2 (en) | 2013-09-09 | 2021-03-02 | Merck Sharp & Dohme Corp. | Treating infections with ceftolozane/tazobactam in subjects having impaired renal function |
| US8906898B1 (en) | 2013-09-27 | 2014-12-09 | Calixa Therapeutics, Inc. | Solid forms of ceftolozane |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0664117A1 (en) | 1995-07-26 |
| RU95101041A (en) | 1997-02-27 |
| ZA95404B (en) | 1995-07-25 |
| AU1029895A (en) | 1995-08-03 |
| JPH07206713A (en) | 1995-08-08 |
| BR9500296A (en) | 1995-10-17 |
| KR950031041A (en) | 1995-12-18 |
| AU699142B2 (en) | 1998-11-26 |
| NZ270362A (en) | 1996-10-28 |
| CN1111125A (en) | 1995-11-08 |
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