JP6752868B2 - 制御薬物放出リポソーム組成物 - Google Patents
制御薬物放出リポソーム組成物 Download PDFInfo
- Publication number
- JP6752868B2 JP6752868B2 JP2018229116A JP2018229116A JP6752868B2 JP 6752868 B2 JP6752868 B2 JP 6752868B2 JP 2018229116 A JP2018229116 A JP 2018229116A JP 2018229116 A JP2018229116 A JP 2018229116A JP 6752868 B2 JP6752868 B2 JP 6752868B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- pharmaceutically acceptable
- vinorelbine
- counterion donor
- dextran sulfate
- 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.)
- Active
Links
- 239000002502 liposome Substances 0.000 title claims description 64
- 239000000203 mixture Substances 0.000 title claims description 19
- 238000013267 controlled drug release Methods 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims description 47
- -1 cationic ion Chemical class 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 29
- 229940124597 therapeutic agent Drugs 0.000 claims description 25
- 229960000633 dextran sulfate Drugs 0.000 claims description 24
- 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 16
- 150000003904 phospholipids Chemical class 0.000 claims description 14
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 13
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 13
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 13
- 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 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 9
- 235000012000 cholesterol Nutrition 0.000 claims description 8
- 150000002500 ions Chemical class 0.000 claims description 7
- 229920002307 Dextran Polymers 0.000 claims description 5
- 229960002086 dextran Drugs 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- 230000003796 beauty Effects 0.000 claims 1
- 229960002066 vinorelbine Drugs 0.000 description 42
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 42
- 239000008194 pharmaceutical composition Substances 0.000 description 32
- 206010028980 Neoplasm Diseases 0.000 description 29
- 125000000524 functional group Chemical group 0.000 description 26
- 230000014759 maintenance of location Effects 0.000 description 26
- 238000000034 method Methods 0.000 description 23
- 241000699670 Mus sp. Species 0.000 description 19
- 125000000129 anionic group Chemical group 0.000 description 18
- 238000005538 encapsulation Methods 0.000 description 16
- 201000011510 cancer Diseases 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 125000002091 cationic group Chemical group 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 206010059516 Skin toxicity Diseases 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 231100000438 skin toxicity Toxicity 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 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 description 9
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 description 8
- 230000001093 anti-cancer Effects 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 150000002632 lipids Chemical class 0.000 description 7
- KLFKZIQAIPDJCW-HTIIIDOHSA-N Dipalmitoylphosphatidylserine Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCC KLFKZIQAIPDJCW-HTIIIDOHSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 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 description 6
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 6
- 239000001166 ammonium sulphate Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 231100000682 maximum tolerated dose Toxicity 0.000 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 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- IBUKXRINTKQBRQ-KCKFLZCVSA-N 1,2-dihexadecanoyl-sn-glycero-3-phospho-D-myo-inositol Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC)COP(O)(=O)O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O IBUKXRINTKQBRQ-KCKFLZCVSA-N 0.000 description 4
- SLKDGVPOSSLUAI-PGUFJCEWSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCCCC SLKDGVPOSSLUAI-PGUFJCEWSA-N 0.000 description 4
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- 102000001301 EGF receptor Human genes 0.000 description 4
- 108060006698 EGF receptor Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- 229940122803 Vinca alkaloid Drugs 0.000 description 4
- 150000007942 carboxylates Chemical class 0.000 description 4
- 230000010261 cell growth Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 4
- 235000011180 diphosphates Nutrition 0.000 description 4
- 235000013601 eggs Nutrition 0.000 description 4
- 150000004676 glycans Chemical class 0.000 description 4
- 229920001477 hydrophilic polymer Polymers 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 230000002746 orthostatic effect Effects 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 229920001282 polysaccharide Polymers 0.000 description 4
- 239000005017 polysaccharide Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 3
- 235000010469 Glycine max Nutrition 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 3
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 3
- 229920000747 poly(lactic acid) Polymers 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 229910021653 sulphate ion Inorganic materials 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- FEPBITJSIHRMRT-UHFFFAOYSA-N 4-hydroxybenzenesulfonic acid Chemical compound OC1=CC=C(S(O)(=O)=O)C=C1 FEPBITJSIHRMRT-UHFFFAOYSA-N 0.000 description 2
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 102000012406 Carcinoembryonic Antigen Human genes 0.000 description 2
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 2
- 229920001287 Chondroitin sulfate Polymers 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 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 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 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 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 208000032023 Signs and Symptoms Diseases 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- FQZQXPXKJFOAGE-KICCZPNWSA-N [(2r)-3-[hydroxy-[(5r)-2,3,4,5,6-pentahydroxycyclohexyl]oxyphosphoryl]oxy-2-octadecanoyloxypropyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)COP(O)(=O)OC1C(O)C(O)C(O)[C@@H](O)C1O FQZQXPXKJFOAGE-KICCZPNWSA-N 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 150000001642 boronic acid derivatives Chemical class 0.000 description 2
- 150000001649 bromium compounds Chemical class 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 229940059329 chondroitin sulfate Drugs 0.000 description 2
- 150000001913 cyanates Chemical class 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000013345 egg yolk Nutrition 0.000 description 2
- 210000002969 egg yolk Anatomy 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 150000004679 hydroxides Chemical class 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 150000002484 inorganic compounds Chemical class 0.000 description 2
- 229910010272 inorganic material Inorganic materials 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 201000005249 lung adenocarcinoma Diseases 0.000 description 2
- 229910001425 magnesium ion Inorganic materials 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 229910001437 manganese ion Inorganic materials 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 150000002823 nitrates Chemical class 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 150000003905 phosphatidylinositols Chemical class 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 229910001415 sodium ion Inorganic materials 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical class CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- WTBFLCSPLLEDEM-JIDRGYQWSA-N 1,2-dioleoyl-sn-glycero-3-phospho-L-serine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC WTBFLCSPLLEDEM-JIDRGYQWSA-N 0.000 description 1
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 description 1
- DGHHQBMTXTWTJV-BQAIUKQQSA-N 119413-54-6 Chemical compound Cl.C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 DGHHQBMTXTWTJV-BQAIUKQQSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 description 1
- 229920000045 Dermatan sulfate Polymers 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical class OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 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 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- AVJBPWGFOQAPRH-FWMKGIEWSA-N alpha-L-IdopA-(1->3)-beta-D-GalpNAc4S Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@H](OS(O)(=O)=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](C(O)=O)O1 AVJBPWGFOQAPRH-FWMKGIEWSA-N 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229920006187 aquazol Polymers 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000005841 biaryl group Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000009295 crossflow filtration Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000002704 decyl group Chemical group [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])* 0.000 description 1
- 229940051593 dermatan sulfate Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-O diethylammonium Chemical compound CC[NH2+]CC HPNMFZURTQLUMO-UHFFFAOYSA-O 0.000 description 1
- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- QPJBWNIQKHGLAU-IQZHVAEDSA-N ganglioside GM1 Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@H](NC(=O)CCCCCCCCCCCCCCCCC)[C@H](O)\C=C\CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)[C@@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](CO)O1 QPJBWNIQKHGLAU-IQZHVAEDSA-N 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000001400 nonyl 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])[H] 0.000 description 1
- 239000003865 nucleic acid synthesis inhibitor Substances 0.000 description 1
- 125000002347 octyl 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])[H] 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920002432 poly(vinyl methyl ether) polymer Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- DRDCQJADRSJFFD-UHFFFAOYSA-N tris-hydroxymethyl-methyl-ammonium Chemical class OC[N+](C)(CO)CO DRDCQJADRSJFFD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000002691 unilamellar liposome Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Images
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
- A61K9/10—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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/721—Dextrans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/24—Apocynaceae (Dogbane family), e.g. plumeria or periwinkle
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/906—Drug delivery
- Y10S977/907—Liposome
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Dispersion Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Biotechnology (AREA)
- Alternative & Traditional Medicine (AREA)
- Biophysics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本願は、その開示全体を参照により本明細書に援用する2013年3月15日に出願された米国特許出願第61/792,850号の利益を主張するものである。
上記で使用したように、本開示を通して、以下の用語は、別段の記載がない限り、以下の意味を有すると理解すべきである。
本明細書では「リポソーム」という用語は、多胞体リポソーム(MVL)、多層小胞(MLV)又は小さい若しくは大きい単層小胞(ULV)を意味する。リポソームは、ナノサイズであり、粒子形成成分及び薬剤輸送成分を含む。粒子形成成分は、封入された脂質関門を形成し、薬剤輸送成分は、粒子形成成分によって封入された媒体を含む。
治療薬は、任意の適切な治療薬とすることができる。一実施形態においては、治療薬は抗癌剤である。抗癌剤の非限定的例としては、ビンカアルカロイド、トポイソメラーゼ阻害剤、タキサン化合物、それらの誘導体、又は薬学的に許容されるそれらの塩が挙げられる。
一実施形態においては、治療薬は、正味正電荷を有する両親媒性塩基であり、リポソーム内の一価対イオン供与体は、アニオン性イオン、又はアニオン性官能基と共有結合した実体から選択することができる。アニオン性イオン又はアニオン性官能基の原子価は、−1、−2又は−3である。
一実施形態においては、治療薬は、両親媒性塩基であり、少なくとも1つの多価対イオン供与体又は薬学的に許容されるその塩は、リポソーム内で不溶性塩を形成する。
一実施形態においては、本発明の医薬組成物は、a)リン脂質又は少なくとも1つのリン脂質とコレステロールの混合物から選択される粒子形成成分を有する少なくとも1つのリポソーム、b)少なくとも1つの多価対イオン供与体又は薬学的に許容されるその塩、(c)少なくとも1つの一価対イオン供与体又は薬学的に許容されるその塩、及び(d)両親媒性治療薬、その誘導体、又は薬学的に許容されるその塩の組合せを含む。
本発明は、有効量の本明細書に記載の医薬組成物をそれを必要とする対象に投与し、それによって癌の症候及び徴候及び/又は対象における毒性が軽減されるステップを含む、対象における癌細胞増殖を阻害する方法を対象とする。
リポソームを溶媒注入法によって調製した。DSPC、DSPE−PEG2000及びコレステロールを含む脂質をモル比3:0.045:2で化合させ、フラスコ中で99.9%エタノールに約60℃で溶解させた。卓上超音波浴を脂質溶解に使用した。
実施例1のリポソームを硫酸アンモニウム一価対イオン供与体と混合して医薬組成物を調製した。ビノレルビンの遠隔充填(remote loading)のために、300mM及び600mM硫酸アンモニウムを使用してリポソームの脂質二分子膜を横切る勾配を設定した。リポソームビノレルビンの封入(充填)効率及び保持プロファイルをインビトロ血漿遊離法によって評価し、結果を表1にまとめた。
分子量8,000(8K)ダルトンのデキストラン硫酸ナトリウムをDOWEXイオン交換カラムによってデキストラン硫酸アンモニウム(デキストラン硫酸の薬学的に許容される塩)に転化した。実施例1のリポソームをそれぞれ4mM及び8mMデキストラン硫酸アンモニウムと混合し、続いてビノレルビン約2mgを遠隔充填し、約60℃でインキュベートすることによって、2種類の医薬組成物を調製した。
インビトロ試験を実施して、リポソームビノレルビンの保持プロファイルに対する一価と多価対イオン供与体の組合せを評価した。
インビトロ試験を実施して、リポソームビノレルビンの保持プロファイルに対する種々の多価対イオン供与体塩の効果を評価した。
リポソームビノレルビン保持プロファイルに対する多価対イオン供与体の分子量の効果を評価した。実施例1によって調製されたリポソームをそれぞれ硫酸アンモニウム並びに5K及び8Kデキストラン硫酸と混合した。
実施例1のリポソームを種々の濃度の硫酸アンモニウム及び種々の濃度のデキストラン硫酸と混合し、続いてビノレルビンを遠隔充填することによって種々の医薬組成物を調製した。リポソームビノレルビンの封入効率及び保持プロファイルを24時間インビトロ血漿遊離法によって評価し、表6〜8にまとめた。
LV304医薬組成物の生体内抗癌評価をマウスにおいて正所性HT−29ヒト結腸腫瘍モデルを用いて実施した。
・ 腫瘍増殖変化率(%T/C)。これは、以下の式によって計算した。
(腫瘍重量x日目−腫瘍重量0日目)治療/(腫瘍重量x日目−腫瘍重量0日目)対照×100%
・ 0日目の体重と比較した最大体重変化。
・ 平均腫瘍倍加時間(TDT)。これは、腫瘍増殖速度の定量化に広く用いられ、以下の式によって計算される。
(x日目−0日目)
・ x日目は、腫瘍体積が、ステージ分類サイズの2倍になるのに要した時間である。
・ 評価し、表7のパラメータに基づいて段階づけした皮膚毒性スコア。
表8によれば、8日目の腫瘍増殖変化率(%T/C)は、NanoVNB群とLV304群で類似していた(NanoVNBは−41.0%、LV304は−42.4%)。平均腫瘍倍加時間(平均TDT)は、NanoVNB群で>78日、LV304群で67.1日、対照群で7.6日であった。さらに、LV304を投与したマウスは、NanoVNBを投与したマウスよりも副作用が少なかった(体重減少が少なく、皮膚毒性スコアが低い)。
LV304医薬組成物の生体内抗癌評価をマウスにおいて正所性PC14PE6/AS2肺腫瘍モデルを用いて実施した。
NanoNVB群:6匹のマウスに、0日目に単一の静脈内注射としてNanoVNBの最大耐量(MTD)の50%を投与した(1/2MTD=ビノレルビン7.5mg/kg)。
・ 0日目の体重と比較した最大体重変化。
・ 平均生存時間。
LV304医薬組成物の生体内皮膚毒性評価をBALB/cマウスを使用して実施した。マウスは、この試験中すべての時間で飲料水及び食物を自由に摂取した。マウスを以下のように3試験群に無作為化した。
NanoVNB群:6匹のマウスにNanoVNBとして1日ビノレルビン7.5mg/kgを0及び9日目にIV注射し、3及び6日目に5mg/kg注射した。
Claims (5)
- (i)リン脂質、及び、(ii)少なくとも1つのリン脂質とコレステロールとの混合物からなる群から選択される粒子形成成分、
0.1〜10mMのデキストラン硫酸又は薬学的に許容されるその塩、及び
100〜500mMの硫酸アンモニウム
を含む両親媒性治療薬送達用リポソーム。 - 前記デキストラン硫酸の薬学的に許容される塩が(i)デキストラン硫酸及び(ii)カチオン性イオンからなり、前記デキストラン硫酸が前記カチオン性イオンとイオン対を形成している、請求項1に記載のリポソーム。
- 前記カチオン性イオンがカルシウム、マグネシウム、ナトリウム、カリウム、及びNR 4 + (式中、RはH又は有機残基である)及びそれらの混合物からなる群から選択される少なくとも1つのカチオン性イオンを含む、請求項2に記載のリポソーム。
- 前記デキストラン硫酸の薬学的に許容される塩がデキストラン硫酸ナトリウム又はデキストラン硫酸アンモニウムである、請求項1に記載のリポソーム。
- デキストラン硫酸が約1,600ダルトンから約8,000ダルトンの分子量を有する、請求項1〜4のいずれか1項に記載のリポソーム。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361792850P | 2013-03-15 | 2013-03-15 | |
US61/792,850 | 2013-03-15 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016503279A Division JP6449848B2 (ja) | 2013-03-15 | 2014-03-15 | 水性及び非水性区画の両方におけるリポソーム組成物による制御薬物放出プロファイルの操作 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019055985A JP2019055985A (ja) | 2019-04-11 |
JP6752868B2 true JP6752868B2 (ja) | 2020-09-09 |
Family
ID=51537897
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016503279A Active JP6449848B2 (ja) | 2013-03-15 | 2014-03-15 | 水性及び非水性区画の両方におけるリポソーム組成物による制御薬物放出プロファイルの操作 |
JP2018229116A Active JP6752868B2 (ja) | 2013-03-15 | 2018-12-06 | 制御薬物放出リポソーム組成物 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016503279A Active JP6449848B2 (ja) | 2013-03-15 | 2014-03-15 | 水性及び非水性区画の両方におけるリポソーム組成物による制御薬物放出プロファイルの操作 |
Country Status (18)
Country | Link |
---|---|
US (1) | US9700511B2 (ja) |
EP (1) | EP2968146B1 (ja) |
JP (2) | JP6449848B2 (ja) |
KR (1) | KR101925507B1 (ja) |
CN (2) | CN105392474B (ja) |
AU (1) | AU2014233308B2 (ja) |
BR (1) | BR112015023481B1 (ja) |
CA (1) | CA2906149C (ja) |
DK (1) | DK2968146T3 (ja) |
ES (1) | ES2777223T3 (ja) |
HK (1) | HK1216010A1 (ja) |
NZ (1) | NZ711500A (ja) |
PL (1) | PL2968146T3 (ja) |
RU (1) | RU2712157C2 (ja) |
SG (2) | SG11201507110WA (ja) |
TW (2) | TWI592168B (ja) |
WO (1) | WO2014145187A1 (ja) |
ZA (1) | ZA201506214B (ja) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10220095B2 (en) * | 2013-03-15 | 2019-03-05 | Taiwan Liposome Company, Ltd | Controlled drug release liposome compositions and methods thereof |
EP3177269A4 (en) * | 2014-08-04 | 2018-02-28 | Zoneone Pharma, Inc. | Remote loading of sparingly water-soluble drugs into lipid vesicles |
KR20190122676A (ko) * | 2017-01-18 | 2019-10-30 | 테마섹 라이프 사이언스 래보러토리 리미티드 | 유사분열기세포의 표적화를 증가시키는 고안정화된 리포좀 |
US20210275447A1 (en) * | 2018-09-10 | 2021-09-09 | Taiwan Liposome Co., Ltd. | Sustained-release ophthalmic pharmaceutical compositions and uses thereof |
US20220054455A1 (en) * | 2018-09-13 | 2022-02-24 | Taiwan Liposome Co., Ltd. | Sustained-release pharmaceutical compositions comprising of a sedative drug and uses thereof |
US20210393524A1 (en) * | 2018-10-17 | 2021-12-23 | Taiwan Liposome Co., Ltd. | Sustained-release pharmaceutical compositions comprising an immunomodulating agent and uses thereof |
CN109260155B (zh) * | 2018-11-05 | 2021-04-06 | 杭州高田生物医药有限公司 | 伊立替康脂质体制剂及其制备与应用 |
WO2023051799A1 (zh) * | 2021-09-30 | 2023-04-06 | 上海济煜医药科技有限公司 | 一种酒石酸长春瑞滨脂质体及其原料组合物、制备方法和应用 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20010051183A1 (en) * | 1989-10-20 | 2001-12-13 | Alza Corporation | Liposomes with enhanced circulation time and method of treatment |
US6723338B1 (en) * | 1999-04-01 | 2004-04-20 | Inex Pharmaceuticals Corporation | Compositions and methods for treating lymphoma |
WO2003018018A2 (en) | 2001-08-24 | 2003-03-06 | Neopharm, Inc. | Vinorelbine compositions and methods of use |
GB0312309D0 (en) | 2003-05-29 | 2003-07-02 | Gaslini Children S Hospital G | Targeted liposome |
EP1557429A1 (en) * | 2004-01-23 | 2005-07-27 | Vectron Therapeutics AG | Site-directed coupling of proteins |
ES2967961T3 (es) * | 2004-05-03 | 2024-05-06 | Ipsen Biopharm Ltd | Liposomas útiles en la administración de fármacos |
WO2006051549A2 (en) * | 2004-11-15 | 2006-05-18 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Combination therapy associating preferably a ceramide with a cytotoxic drug |
AU2006307460A1 (en) * | 2005-10-26 | 2007-05-03 | New York University | A method for preparing liposomes and uses thereof |
CN100375621C (zh) | 2005-11-04 | 2008-03-19 | 唐星 | 长春瑞滨脂质微球注射液及其制备方法 |
CN100438855C (zh) | 2006-01-19 | 2008-12-03 | 浙江大学 | 重酒石酸长春瑞滨脂质体及其冻干粉针与制备方法 |
CN100998562A (zh) | 2006-12-31 | 2007-07-18 | 西安力邦医药科技有限责任公司 | 注射用长春瑞滨脂质体的制备方法 |
CN101129375B (zh) | 2007-07-06 | 2010-12-22 | 浙江大学 | 长春瑞滨固体脂质纳米粒与其冻干制剂及制备方法 |
TW200922630A (en) * | 2007-09-26 | 2009-06-01 | Nat Health Research Institutes | Liposome compositions useful for tumor imaging and treatment |
CN101933904B (zh) | 2009-07-01 | 2011-11-16 | 齐鲁制药有限公司 | 一种长春瑞滨长循环脂质体制剂及其制备方法 |
WO2011092708A2 (en) | 2010-02-01 | 2011-08-04 | Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. | Liposomes comprising amphipathic drugs and method for their preparation |
CN101849915A (zh) | 2010-05-26 | 2010-10-06 | 辽宁中医药大学 | 异长春花碱隐形脂质体冻干粉针剂及其制备方法 |
CN101843584B (zh) | 2010-06-02 | 2012-05-30 | 北京大学 | 一种全反式维甲酸与脂质体的复合物及其应用 |
-
2014
- 2014-03-15 BR BR112015023481-0A patent/BR112015023481B1/pt active IP Right Grant
- 2014-03-15 AU AU2014233308A patent/AU2014233308B2/en active Active
- 2014-03-15 JP JP2016503279A patent/JP6449848B2/ja active Active
- 2014-03-15 SG SG11201507110WA patent/SG11201507110WA/en unknown
- 2014-03-15 CN CN201480010159.XA patent/CN105392474B/zh active Active
- 2014-03-15 WO PCT/US2014/029907 patent/WO2014145187A1/en active Application Filing
- 2014-03-15 DK DK14764361.3T patent/DK2968146T3/da active
- 2014-03-15 KR KR1020157024828A patent/KR101925507B1/ko active IP Right Grant
- 2014-03-15 PL PL14764361T patent/PL2968146T3/pl unknown
- 2014-03-15 CN CN201811606602.6A patent/CN109350600B/zh active Active
- 2014-03-15 EP EP14764361.3A patent/EP2968146B1/en active Active
- 2014-03-15 US US14/774,833 patent/US9700511B2/en active Active
- 2014-03-15 RU RU2015135629A patent/RU2712157C2/ru active
- 2014-03-15 CA CA2906149A patent/CA2906149C/en active Active
- 2014-03-15 SG SG10201707474XA patent/SG10201707474XA/en unknown
- 2014-03-15 ES ES14764361T patent/ES2777223T3/es active Active
- 2014-03-15 NZ NZ711500A patent/NZ711500A/en unknown
- 2014-03-17 TW TW103110057A patent/TWI592168B/zh active
- 2014-08-11 TW TW103127491A patent/TWI660749B/zh active
-
2015
- 2015-08-26 ZA ZA2015/06214A patent/ZA201506214B/en unknown
-
2016
- 2016-04-07 HK HK16103949.8A patent/HK1216010A1/zh unknown
-
2018
- 2018-12-06 JP JP2018229116A patent/JP6752868B2/ja active Active
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6752868B2 (ja) | 制御薬物放出リポソーム組成物 | |
JP7355394B2 (ja) | カロテノイド組成物およびその使用 | |
US11147881B2 (en) | Controlled drug release liposome compositions and methods thereof | |
JP5570994B2 (ja) | 治療薬を含有する新規な温度感受性リポソーム | |
CN103479578B (zh) | 一种马来酸匹杉琼的脂质体制剂及其制备工艺 | |
KR20210003197A (ko) | 폐 질환 치료에 사용하기 위한 흡입 가능한 리포솜 서방형 조성물 | |
JPWO2020071349A1 (ja) | 薬物を内包するリポソーム組成物およびプラチナ製剤を含む組合せ医薬 | |
BR102017018582A2 (pt) | Lipossomas, processo de obtenção, composições antitumorais e usos | |
CN112004527B (zh) | 用于治疗肺部疾病的可吸入脂质体缓释组合物 | |
TW202320803A (zh) | 製備脂質體調配物之方法 | |
OA20783A (en) | Carotenoid compositions and uses thereof | |
Raikwar et al. | Nano-Based Drug Delivery System: An Overview and Future Prospective |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20181225 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20181225 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200204 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200430 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200728 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200819 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6752868 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |