CN1422619A - 高不溶性铂配合物的脂质复合物和脂质体 - Google Patents
高不溶性铂配合物的脂质复合物和脂质体 Download PDFInfo
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- CN1422619A CN1422619A CN02150455A CN02150455A CN1422619A CN 1422619 A CN1422619 A CN 1422619A CN 02150455 A CN02150455 A CN 02150455A CN 02150455 A CN02150455 A CN 02150455A CN 1422619 A CN1422619 A CN 1422619A
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- diamino
- cyclohexane
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 69
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 37
- 150000002632 lipids Chemical class 0.000 title claims abstract description 32
- 239000000203 mixture Substances 0.000 title claims abstract description 26
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 25
- 239000002502 liposome Substances 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 3
- -1 diamino-cyclohexane-malonic acid platinum Chemical compound 0.000 claims description 22
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 21
- 238000004108 freeze drying Methods 0.000 claims description 21
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 claims description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 claims description 11
- LHLPWFBHDVYBGD-UHFFFAOYSA-N 4,4-diaminocyclohexane-1,1-dicarboxylic acid Chemical class NC1(CCC(CC1)(C(=O)O)C(=O)O)N LHLPWFBHDVYBGD-UHFFFAOYSA-N 0.000 claims description 10
- 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 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 235000011187 glycerol Nutrition 0.000 claims description 9
- 150000001991 dicarboxylic acids Chemical class 0.000 claims description 8
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 235000012000 cholesterol Nutrition 0.000 claims description 5
- 238000001246 colloidal dispersion Methods 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 3
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 3
- 241001597008 Nomeidae Species 0.000 claims description 2
- 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 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229960005160 dimyristoylphosphatidylglycerol Drugs 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 12
- 238000000034 method Methods 0.000 abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 10
- 239000006185 dispersion Substances 0.000 description 10
- YMHQVDAATAEZLO-UHFFFAOYSA-N cyclohexane-1,1-diamine Chemical compound NC1(N)CCCCC1 YMHQVDAATAEZLO-UHFFFAOYSA-N 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical group [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002131 composite material Substances 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 6
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000008365 aqueous carrier Substances 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- UIKBVAKLSYCDON-UHFFFAOYSA-N cyclohexane-1,1-diamine platinum(2+) dinitrate Chemical compound [Pt++].[O-][N+]([O-])=O.[O-][N+]([O-])=O.NC1(N)CCCCC1 UIKBVAKLSYCDON-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- ZYZCZCHRQQZTHI-UHFFFAOYSA-N cyclohexane-1,1-diamine;platinum Chemical compound [Pt].NC1(N)CCCCC1 ZYZCZCHRQQZTHI-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 150000003057 platinum Chemical class 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 229910001961 silver nitrate Inorganic materials 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 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
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 2
- 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 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- SMHRYINYIIPKQB-UHFFFAOYSA-L cyclohexane-1,1-diamine;diiodoplatinum Chemical compound I[Pt]I.NC1(N)CCCCC1 SMHRYINYIIPKQB-UHFFFAOYSA-L 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 239000008384 inner phase Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 150000003058 platinum compounds Chemical class 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- JLVSRWOIZZXQAD-UHFFFAOYSA-N 2,3-disulfanylpropane-1-sulfonic acid Chemical compound OS(=O)(=O)CC(S)CS JLVSRWOIZZXQAD-UHFFFAOYSA-N 0.000 description 1
- MCRZWYDXIGCFKO-UHFFFAOYSA-N 2-butylpropanedioic acid Chemical compound CCCCC(C(O)=O)C(O)=O MCRZWYDXIGCFKO-UHFFFAOYSA-N 0.000 description 1
- 101710134784 Agnoprotein Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920001503 Glucan Polymers 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
- 229920001612 Hydroxyethyl starch Polymers 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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 229920000305 Nylon 6,10 Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000012752 auxiliary agent 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036760 body temperature Effects 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- BIABMEZBCHDPBV-UHFFFAOYSA-N dipalmitoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
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- 238000004090 dissolution Methods 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
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- 239000003792 electrolyte Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940027278 hetastarch Drugs 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000001419 myristoyl group Chemical group O=C([*])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 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 229910052756 noble gas Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 1
- LULRWFILUQGIDA-UHFFFAOYSA-N platinum;propanedioic acid Chemical compound [Pt].OC(=O)CC(O)=O LULRWFILUQGIDA-UHFFFAOYSA-N 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000001038 titanium pigment Substances 0.000 description 1
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Classifications
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- 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
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
- A61K47/6911—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种高不溶性铂配合物的脂质复合物和脂质体,更具体地说,本发明涉及一种二羧酸铂的磷脂复合物,含有它的药物组合物以及所述组合物的制备方法。
Description
本发明涉及一种高不溶性铂配合物的脂质复合物和脂质体，更具体地说，本发明涉及一种二羧酸铂的磷脂复合物，采用或不采用冷冻干燥技术可将其配制在药学上可接受的载体中，并将其给药于患有癌症和其它疾病的患者。
某此铂配合物已显示出对癌症具有优异的活性。但是，由于这些配合物不能溶解于药学上可接受的载体，其临床应用受到了极大的限制。例如，业已表明，二氨基环己烷(DACH)与铂化合物的配合物对几种类型的癌症均具有活性。然而，DACH-铂配合物几乎不溶于含水载体中和多数有机溶剂中。DACH-铂不溶于有机溶剂妨碍其通过已知方法在脂质体中的包囊或在脂质复合物中的应用。
因而，人们仍希望能制备出高不溶性物质如DACH-铂配合物的增溶的并且药学上稳定的形式。
发明概述
本发明的目的是提供一种水不溶性铂配合物的可溶性、药学上可接受的剂型。
本发明的另一个目的是提供二氨基环己烷-铂配合物的磷脂复合物或脂质体。
本发明的另一个目的是提供一种冷冻干燥的二氨基环己烷-铂-磷脂复合物或脂质体冷冻干燥的药学上可接受的剂型。
以下，将详细描述本发明二氨基环己烷-丙二酸铂的脂质复合物或脂质体的制备方法和二氨基环己烷-丙二酸铂的脂质复合物的冷冻干燥物的制备方法，本领域的技术人员易于理解，本文所述方法也适用于制备其它被认为是水不溶性且不能通过注射或输注方式给药的铂配合物的脂质复合物或脂质体和冷冻干燥物。
按照本发明的一个具体实施方案，提供了能与药学上可接受的水性稀释剂如水进行配制以用于注射的二氨基环己烷-二羧酸铂的磷脂复合物或脂质体。
DACH-二羧酸铂的可溶性磷脂复合物可通过下述方法就地制备：使DACH与四氯铂酸钾和碘化钾反应形成DACH-碘化铂，再使DACH-碘化铂与硝酸银反应得到DACH-硝酸铂。然后，使DACH-硝酸铂同时与磷脂氯仿/乙醇溶液和羧酸反应，形成DACH-二羧酸铂的脂质复合物产品。业已发现，铂配合物的羧酸化可极大地降低其水溶解性。根据本发明，通过延缓羧酸化反应直至形成脂质复合物或脂质体时，则可以保持铂化合物的溶解性，从而使配合物的溶液可用于形成脂质复合物或脂质体。
本发明的DACH-二羧酸铂也可以制成脂质体。脂质体广泛描述在现有技术的文献中，其结构也是公知的。本发明中，脂质体这样制备：形成活性成分的膜，本发明中活性成分为DACH-硝酸铂和磷脂，加入羧酸，然后将磷脂的溶剂如氯仿/乙醇蒸发，得到所述膜，加入注射用水，最后对形成的脂质体进行均化处理。发明详述
术语“脂质复合物”是在制备药用化合物中常规采用的术语。脂质复合物的特征是，在脂质与药用化合物间为非共价键，在示差扫描量热法中可观察到相变。
本文中，术语“药学上可接受的水性稀释剂”是指注射用水、盐水和其它公知的水性载体。
术语“冷冻干燥赋形剂”是指在冷冻干燥前加入溶液中以增强诸如干燥块的颜色、组织、强度和体积等特性的物质。冷冻干燥赋形剂的实例在下面描述。
按照本发明的一种实施方案，根据下述反应路线制备二氨基环己烷铂配合物的脂质复合物：
如上面第一步所述，二氨基环己烷(1)、四氯铂酸钾(2)和碘化钾(3)以化学计量量在水中进行反应，得到二氨基环己烷-碘化铂(4)，这种产物仅微溶解于水中。向二氨基环己烷-碘化铂(4)中加入硝酸银溶液(5)，形成二氨基环己烷-硝酸铂(6)。二氨基环己烷-硝酸铂(6)可溶于水，但因其会造成肾中毒，因而不能用作抗肿瘤药。向二氨基环己烷-硝酸铂(6)中加入适宜的磷脂(7)，并同时加入过量的二羧酸(8)如丙二酸(用于说明)，所述磷脂优选为二肉豆蔻酰磷脂酰胆碱与二肉豆蔻酰磷脂酰甘油的混合物的氯仿/乙醇溶液。在通过氮气吹扫除去氯仿/乙醇后，形成二氨基环己烷-二羧酸铂，其同时与磷脂(7)配合。然后，对二氨基环己烷-二羧酸铂产物(9)进行离心处理，再悬浮于注射用水中。上述过程涉及制备DACH配合物，本领域的技术人员易于理解，可采用其它配位体或螯合剂以制备其它配合物。
用于制备二氨基环己烷-二羧酸铂的羧酸包括：草酸、丙二酸、琥珀酸、戊二酸、己二酸、庚二酸、马来酸、富马酸、壬二酸、辛二酸、癸二酸、酒石酸、邻苯二甲酸等。这些酸可被取代或未被取代。本发明中，优选采用丙二酸。
用于本发明的二氨基环己烷-二羧酸铂具有下述结构式：其中，R1和R2相同或不同，代表氢、C1-C10烷基、C6-C10芳基、C7-C18烷芳基、C7-C18芳烷基，或者，R1和R2可形成取代或未取代的、饱和或不饱和的4、5或6元环；或者，R1或R2可与相邻碳原子上的R1或R2结合形成取代或未取代的、饱和或不饱和的4、5或6元环；n为0-10。
二氨基环己烷-二羧酸铂通常为二氨基环己烷-草酸铂、二氨基环己烷-丙二酸铂、二氨基环己烷-琥珀酸铂、二氨基环己烷-戊二酸铂、二氨基环己烷-己二酸铂、二氨基环己烷-庚二酸铂、二氨基环己烷-马来酸铂、二氨基环己烷-富马酸铂、二氨基环己烷-邻苯二甲酸铂和二氨基环己烷-酒石酸铂等。优选的二氨基环己烷-二羧酸铂为二氨基环己烷-丙二酸铂或丙二酸部分被诸如烷基如丁基取代的二氨基环己烷-丙二酸铂。
用于制备磷脂溶液的有机溶剂必须与磷酸相容，不能使磷脂或DACH-硝酸铂配合物去稳定。此外，脂质应能充分溶解于溶剂中，从而能使足够的脂质形成复合物，并尽可能减少以后必须除去的溶剂用量。最优选易于从脂质复合物的分散体中除去的挥发性或低熔点溶剂。最典型的用于制备这种溶液的溶剂是氯仿、乙醇或二氯甲烷或其混合物。氯仿和乙醇的混合物在本发明中可得到良好的结果。
磷脂天然具有两亲性，即，磷脂分子具有疏水端基如长链烃基和亲水头。在水性介质如水或盐水中，尾端相互间排列，远离水分子，而亲水头则朝向水相。正是磷脂的这一性质使其特别适用于配制像本发明的高不溶性药物。
应对用于本发明的磷脂进行选择以使其相转变温度约等于或低于体温或约37℃。有用的磷脂的代表性实例包括：合成磷脂二肉豆蔻酰磷脂酰胆碱(DMPC)、二肉豆蔻酰磷脂酰甘油(DMPG)、二棕榈酰磷脂酰胆碱(DPPC)、二棕榈酰磷脂酰甘油(DPPG)、二硬脂酰磷脂酰胆碱(DSPC)、二硬脂酰磷脂酰甘油(DSPG)，或其混合物。其它磷脂的实例在下述文献中有述：
CRC脂盾双层手册，Marsh，M.A.，CRC出版社(1990)。当采用DMPC和DMPG时，DMPC与DMPG的比例为约7∶3，它们模拟了细胞膜。
将脂质溶液加至DACH-硝酸铂溶液中，从而使DACM-硝酸铂与脂质的重量比为约1∶80至1∶5，优选约1∶80至1∶10，更优选约1∶45至1∶25。
在某些应用时，发现向脂质复合物中加入胆固醇或其半琥珀酸酯衍生物是有利的。据信，胆固醇可使双层包裹得更加紧密，从而减缓了药物的释放。这一措施对皮下制剂是特别有用的，在此情形下，如果药物输送得太快，则可能导致严重坏死。胆固醇被加至磷脂溶液中。胆固醇的用量可为约0.5至15份/100份磷脂。
本领域公知的各种技术均可用于从脂质-DACH-二羧酸铂复合物中除去溶剂。例如，可通过用惰性气体如氮气进行吹扫以方便地除去如前讨论的氯仿/乙醇混合物。
DACH-二羧酸铂的磷酸复合物可悬浮于药学上可接受的载体如注射用水中，或者，该配合物也可采用药学上可接受的冷冻干燥赋形剂将其冷冻干燥。甘露糖醇为常规采用的赋形剂，但也可采用其它不与药物或脂质复合物反应的其它赋形剂。也可以用于本发明的普通赋形剂的实例为磷酸钾或钠、柠檬酸、酒石酸、明胶和碳水化合物如乳糖、葡萄糖、葡聚糖、羟乙基淀粉等。赋形剂可单独使用或组合使用以得到易于在复配时分散于水中的具有优良质量的块状物。
赋形剂通常以水溶液形式加至分散体中。另外，希望使用浓溶液以减少在冷冻干燥时须除去的水量。赋形剂的用量可以本领域公知的方式进行调节，以得到不会裂开或收缩的块状物，并且，这种块状物为多孔材料，易于溶解，并具有优良的外观。已发现甘露糖醇是有用的。甘露糖醇以浓度为约5至150g/ml的溶液加至分散体中。以1份磷脂-DACH-二羧酸铂复合物计，甘露糖醇的用量为约1至100重量份。
在除去溶剂及加入赋形剂后，将分散体用均质器进行均化处理(可采用Tekmar转子/定子均质器，T25型，或者采用microfluidics浸入喷射式均质器，M110Y型)。一般而言，分散体的颗粒尺寸越小，则在冷冻干燥循环中制剂干燥得越快。分散体的粒径分布范围为约10-500nm，平均为约250nm时，可获得满意的冷冻干燥结果。最佳的粒径可根据给药的方式改变。
用于本发明的常规冷冻干燥过程在下面提供。该过程可按本领域技术人员公知的方法根据设置和设施进行改变。
均质后的制剂可倒入标称容积5-50ml的小瓶中。将这种小瓶放置在约5℃的冷冻干燥室中。通常，应选择小瓶的容积以使每一支小瓶包含单一剂量的磷脂-DACH-二羧酸铂。在1小时内，将干燥室的温度降低至-30℃，此后，将温度保持在-30℃下约4小时。然后，将冷冻干燥室的压力减少至200-250微米，并在冷冻过程中保持该压力。在冷冻室压力降低后，将温度在15小时内升高至25℃，将产品在25℃下保持5小时。再在20分钟内将温度升至40℃，并在该温度下放置2小时。冷冻干燥后产品的最终含水量小于约5％，优选约1-2％。
对于静脉内给药或皮下给药而言，复合物可采用水性载体如水、盐水或另一种电解质进行复配。冷冻干燥的产品加入水后得到一种脂质复合物在赋形剂水溶液中的胶态分散体。复合物或脂质均不溶于水。胶态分散体由至少两种不同相组成。第一相为分散相或内相。第二相为连续相或外相。在胶态下的体系包含一种或多种至少尺寸为10-100埃至几个微米的物质。参见下述文献：Remington药物科学-分散系统(Disnerse Systems，
Remington’s Pharmaceutical Sciences，18版，19章，272-4页，MackPublishing Company，Easton，PA 18042)。在本发明的胶态分散体中，分散相或内相包含磷脂-DACH-二羧酸铂复合物，其粒径为约10-1000nm。在选择水性载体时，推荐使用比重约等于脂质复合物(估计为1.08g/cc)的那些，以减少分散体分离的可能性。
脂质复合物的冷冻干燥物可用水、盐水或其它用于静脉内给药的药学上可接受水性稀释剂复配。在复配后，得到适于进行注射的分散体。冷冻干燥物也可以含水分散体或以糊剂口服给药。
对于口服给药而言，冷冻干燥物可复配形成口服分散体或配制成糊剂。或者，冷冻干燥物可填充入软明胶胶囊中用于口服给药。
磷脂-DACH-二羧酸铂复合物以治疗有效量给药。复合物的剂量在文献中已有描述。优选采用可编程连续输液移动式泵，将药物以连续输液形式在3-21天内给药。可以预期，药物将会与粒细胞集落刺激因子(GCSF)一起给药。
虽然磷脂-DACH-二羧酸铂复合物可被冷冻干燥，磷脂-DACH-二羧酸铂复合物是药学上具有活性的，其通常可不经冷冻干燥而配制成用于口服给药、静脉内给药或皮下给药的剂型。制剂助剂如抗菌剂和抗氧化剂可用于增强复合物的稳定性。
磷脂复合物二氨基环己烷二羧酸盐的脂质体可这样制备：将二氨基环己烷硝酸铂的溶液加至适宜的磷脂中，加入二羧酸，蒸发出用于磷脂的溶剂，形成一种脂质体膜，加入注射用水，将形成的脂质体进行均质化。
以下，参考下述非限定性实施例对本发明进行更详细的描述。
实施例1
将20.0g的K2PtCl4(四氯铂酸钾)、54.2g的KI(碘化钾)和5.0g的DACH(二氨基环己烷)溶解于600mL水中，使反应进行1小时。从水中沉淀出产物DACH-PtI2。
将10.8g的AgNO3(硝酸银)溶解于170mL水中。在搅拌下向其中加入17.9g的DACH-PtI2。反应过夜，得到DACH-PtNO3。
向3.1ml DACH-PtNO3溶液(浓度为65mg/ml)中，加入0.1M的氢氧化钠，直至pH值为5.5至5.7。
将4200mg的二肉豆蔻酰磷酰胆碱(DMPS)溶解于8.5ml无水乙醇中。向其中加入1800mg溶解于5ml氯仿中的二肉豆蔻酰磷酰甘油(DMPG)。
制备13％W/V的丙二酸溶液。用氢氧化钠调节pH值为5.5至5.7。
将脂质溶液加热至40-50℃，容器保持覆盖。向该溶液中加入DACH-PtNO3溶液。将内容物搅拌20分钟。然后，除去容器的盖子，使溶剂蒸发。向其中加入25ml的0.9％氯化钠溶液。残存的溶剂通过用氮气吹扫而除去。将脂质复合物的悬浮液补足为50ml。采用Tekmar均化机使粒径减小。
实施例2
重复实施例1的过程，只是采用的二羧酸为丁基丙二酸。
表1说明了DACH-丙二酸铂和DACH-丁基丙二酸铂的磷脂复合物的抗肿瘤活性与顺铂和安慰剂的比较。
基于以上对本发明的详细描述及优选的实施方案，不背离如权利要求书所定义的本发明范围的各种改变和改进均是显而易见的。
表1
DACH-铂化合物对耐铂P388细胞系的抗肿瘤活性
| 制剂 | 剂量(mg/kg) | 平均死亡天数 | ％存活时间增加 | 肿瘤负担变化的Log10值 | ％T/C |
| DACH-丙二酸铂 | 60.040.027.0 | 23.521.020.0 | +80+61+53 | -2.10+0.8 | 180.7161.5153.8 |
| DACH-丁基丙二酸铂 | 60.040.027.0 | 21.521.020.5 | +65+61+57 | -0.40+0.4 | 165.3161.5157.7 |
| 顺铂 | 8.05.33.5 | 16.015.013.6 | +23+15+3 | +1.5+1.5+1.7 | 123.1115.4103.8 |
| 对照(安慰剂)初始肿瘤负担＝1.0×106 | - | 13.0 | - |
Claims (14)
1、一种药物组合物，其包含磷脂与水不溶性二羧酸铂配合物的脂质复合物或脂质体。
2、根据权利要求1的组合物，其中，所述的二羧酸铂为下式的二氨基环己烷-二羧酸铂：其中，R1和R2相同或不同，代表氢、C1-C10烷基、C6-C10芳基、C7-C18烷芳基、C7-C10芳烷基，或者，R1和R2可形成取代或未取代的、饱和或不饱和的4、5或6元环；或者，R1或R2可与相邻碳原子上的R1或R2结合形成取代或未取代的、饱和或不饱和的4、5或6元环；n为0-10。
3、根据权利要求2的组合物，其中，所述的二氨基环己烷-二羧酸铂选自二氨基环己烷-草酸铂、二氨基环己烷-丙二酸铂、二氨基环己烷-琥珀酸铂、二氨基环己烷-戊二酸铂、二氨基环己烷-己二酸铂、二氨基环己烷-庚二酸铂、二氨基环己烷-马来酸铂、二氨基环己烷-富马酸铂、二氨基环己烷-邻苯二甲酸铂和二氨基环己烷-酒石酸铂。
4、根据权利要求3的组合物，其中，所述的二氨基环己烷-二羧酸铂为二氨基环己烷-丙二酸铂。
5、根据权利要求1的组合物，其中，所述磷脂选自二肉豆蔻酰磷脂酰胆碱、二肉豆蔻酰磷脂酰甘油、二棕榈酰磷脂酰胆碱、二棕榈酰磷脂酰甘油、二硬脂酰磷脂酰胆碱、二硬脂酰磷脂酰甘油，或其混合物。
6、根据权利要求5的组合物，其中，所述的磷脂为二肉豆蔻酰磷脂酰胆碱与二肉豆蔻酰磷脂酰甘油的混合物。
7、根据权利要求6的组合物，其中，所述的二肉豆蔻酰磷脂酰胆碱与二肉豆蔻酰磷脂酰甘油在所述混合物中的重量比为约7∶3。
8、根据权利要求1的组合物，其中，当用药学上可接受的含水稀释剂进行配制时，所述的脂质复合物形成胶态分散体。
9、根据权利要求1的组合物，其中，所述的脂质复合物为所述磷脂与所述二羧酸铂的配合物的冷冻干燥物。
10、根据权利要求1的组合物，其中，所述组合物还包含一种药学上可接受的赋形剂。
11、根据权利要求10的组合物，其中，所述的赋形剂为甘露糖醇。
12、根据权利要求9的组合物，其中，所述的组合物还包含胆固醇或其半琥珀酸酯衍生物。
13、根据权利要求9的组合物，其中，当用药学上可接受的水性稀释剂进行配制时，所述的脂质复合物形成胶态分散体。
14、一种药物组合物，其包含二氨基环己烷丙二酸铂和二肉豆蔻酰磷脂酰胆碱(DMPC)和二肉豆蔻酰磷脂酰甘油(DMPG)的复合物，DMPC与DMPG的比例为约7∶3。
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| US3737797P | 1997-02-05 | 1997-02-05 | |
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| CNB021504555A Expired - Fee Related CN1191067C (zh) | 1997-02-05 | 1998-01-28 | 高不溶性铂配合物的脂质复合物和脂质体 |
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| JP (1) | JP2002513396A (zh) |
| KR (1) | KR100578705B1 (zh) |
| CN (2) | CN1096263C (zh) |
| AT (1) | ATE284204T1 (zh) |
| AU (1) | AU749220B2 (zh) |
| BR (1) | BR9815445A (zh) |
| CA (1) | CA2279279C (zh) |
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| PL (1) | PL192633B1 (zh) |
| PT (1) | PT975329E (zh) |
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| US9186322B2 (en) * | 2002-08-02 | 2015-11-17 | Insmed Incorporated | Platinum aggregates and process for producing the same |
| CA2524478A1 (en) * | 2003-05-02 | 2004-11-18 | Aronex Pharmaceuticals, Inc. | Lipid platinum complexes and methods of use thereof |
| CA2526289A1 (en) * | 2003-05-20 | 2004-12-02 | Aronex Pharmaceuticals, Inc. | Combination chemotherapy comprising 5-fluorouracil or a derivative thereof and a liposomal platinum complex |
| WO2004105747A1 (en) * | 2003-05-20 | 2004-12-09 | Aronex Pharmaceuticals, Inc | Combination chemotherapy comprising capecitabine and a liposomal platinum complex |
| AU2003239510A1 (en) * | 2003-05-20 | 2005-01-21 | Aronex Pharmaceuticals, Inc. | Combination chemotherapy comprising gemcitabine and a liposomal platinum complex |
| JP2007504177A (ja) * | 2003-09-02 | 2007-03-01 | プリヴァ−ラケマ，エー．エス． | 医薬組成物、その製造方法及び治療上の使用 |
| CA2560900A1 (en) * | 2004-03-26 | 2005-10-06 | Cell Therapeutics Europe S.R.L. | Nanoparticle formulations of platinum compounds |
| WO2006084248A2 (en) * | 2005-02-04 | 2006-08-10 | Antigenics, Inc. | Compositions comprising a platinum complex, lipid, and surfactant |
| US9107824B2 (en) | 2005-11-08 | 2015-08-18 | Insmed Incorporated | Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally |
| WO2007067784A2 (en) * | 2005-12-08 | 2007-06-14 | Wyeth | Liposomal compositions |
| CZ300424B6 (cs) * | 2006-06-20 | 2009-05-13 | Pliva - Lachema A. S. | Farmaceutická kompozice pro perorální podání |
| JP5759464B2 (ja) | 2009-09-21 | 2015-08-05 | ジェイダブリュー ファーマシューティカル コーポレイション | オキサリプラチンのナノ粒子及びその製造方法 |
| US9387152B2 (en) | 2010-06-28 | 2016-07-12 | The General Hospital Corporation | Blood substitutes and uses thereof |
| CN102276674A (zh) * | 2011-06-24 | 2011-12-14 | 天津大学 | 用于肿瘤靶向治疗的含半乳糖铂配合物及其制备方法 |
| CN102286050A (zh) * | 2011-06-24 | 2011-12-21 | 天津大学 | 用于肿瘤靶向治疗的含葡萄糖铂配合物及其制备方法 |
| CN102286049A (zh) * | 2011-06-24 | 2011-12-21 | 天津谷堆生物医药科技有限公司 | 用于肿瘤治疗的水溶性铂配合物及其制备方法 |
| CN102716145A (zh) * | 2012-06-20 | 2012-10-10 | 天津谷堆生物医药科技有限公司 | 含糖铂配合物在制备防治肿瘤药物的用途 |
| AU2013292636A1 (en) | 2012-07-18 | 2015-02-05 | Onyx Therapeutics, Inc. | Liposomal compositions of epoxyketone-based proteasome inhibitors |
| US11291644B2 (en) | 2012-09-04 | 2022-04-05 | Eleison Pharmaceuticals, Llc | Preventing pulmonary recurrence of cancer with lipid-complexed cisplatin |
| MX2015012199A (es) | 2013-03-13 | 2015-11-30 | Mallinckrodt Llc | Composiciones de cisplatino liposomal para la terapia contra el cancer. |
| CN104546722B (zh) * | 2015-02-10 | 2017-05-24 | 中国医学科学院医药生物技术研究所 | 米铂脂质体和制法 |
| CN109678910B (zh) * | 2016-01-25 | 2021-09-07 | 沈阳药科大学 | 一种化合物及其应用以及一种铂类配合物及其脂质体 |
| US11339209B2 (en) | 2016-11-14 | 2022-05-24 | Novartis Ag | Compositions, methods, and therapeutic uses related to fusogenic protein minion |
| CN114652680A (zh) * | 2020-12-24 | 2022-06-24 | 沈阳药科大学 | 制备脂质体的方法 |
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| EP0113508A1 (en) * | 1982-11-04 | 1984-07-18 | Inco Research & Development Center, Inc. | Hydrophobic platinum compounds and their preparation |
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| US5393909A (en) * | 1988-11-22 | 1995-02-28 | Board Of Regents, The University Of Texas System | Diamine platinum complexes as antitumor agents |
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