JP6180241B2 - シクロデキストリン誘導体及び医薬組成物 - Google Patents
シクロデキストリン誘導体及び医薬組成物 Download PDFInfo
- Publication number
- JP6180241B2 JP6180241B2 JP2013178090A JP2013178090A JP6180241B2 JP 6180241 B2 JP6180241 B2 JP 6180241B2 JP 2013178090 A JP2013178090 A JP 2013178090A JP 2013178090 A JP2013178090 A JP 2013178090A JP 6180241 B2 JP6180241 B2 JP 6180241B2
- Authority
- JP
- Japan
- Prior art keywords
- cells
- porphyrin
- tpps
- cyclodextrin
- pharmaceutical composition
- 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
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 title claims description 34
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 20
- 150000004032 porphyrins Chemical class 0.000 claims description 23
- -1 4-sulfonatophenyl Chemical group 0.000 claims description 8
- 230000002209 hydrophobic effect Effects 0.000 claims description 7
- 150000001450 anions Chemical class 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 48
- PBHVCRIXMXQXPD-UHFFFAOYSA-N chembl2369102 Chemical compound C1=CC(S(=O)(=O)O)=CC=C1C(C1=CC=C(N1)C(C=1C=CC(=CC=1)S(O)(=O)=O)=C1C=CC(=N1)C(C=1C=CC(=CC=1)S(O)(=O)=O)=C1C=CC(N1)=C1C=2C=CC(=CC=2)S(O)(=O)=O)=C2N=C1C=C2 PBHVCRIXMXQXPD-UHFFFAOYSA-N 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 229940079593 drug Drugs 0.000 description 21
- 239000003814 drug Substances 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- 229920000858 Cyclodextrin Polymers 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 230000008859 change Effects 0.000 description 9
- 239000003937 drug carrier Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- BQRGNLJZBFXNCZ-UHFFFAOYSA-N calcein am Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O)=C(OC(C)=O)C=C1OC1=C2C=C(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(=O)C)C(OC(C)=O)=C1 BQRGNLJZBFXNCZ-UHFFFAOYSA-N 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000001254 matrix assisted laser desorption--ionisation time-of-flight mass spectrum Methods 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 230000035699 permeability Effects 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 5
- DEGAKNSWVGKMLS-UHFFFAOYSA-N calcein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(O)=O)CC(O)=O)=C(O)C=C1OC1=C2C=C(CN(CC(O)=O)CC(=O)O)C(O)=C1 DEGAKNSWVGKMLS-UHFFFAOYSA-N 0.000 description 5
- 210000000170 cell membrane Anatomy 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 230000003834 intracellular effect Effects 0.000 description 5
- 229960002378 oftasceine Drugs 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 5
- 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 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 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 3
- 206010034972 Photosensitivity reaction Diseases 0.000 description 3
- AFVLVVWMAFSXCK-VMPITWQZSA-N alpha-cyano-4-hydroxycinnamic acid Chemical compound OC(=O)C(\C#N)=C\C1=CC=C(O)C=C1 AFVLVVWMAFSXCK-VMPITWQZSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 238000002073 fluorescence micrograph Methods 0.000 description 3
- 238000012757 fluorescence staining Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000013508 migration Methods 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 108010038765 octaarginine Proteins 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000002428 photodynamic therapy Methods 0.000 description 3
- 208000007578 phototoxic dermatitis Diseases 0.000 description 3
- 231100000018 phototoxicity Toxicity 0.000 description 3
- 108010011110 polyarginine Proteins 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000032258 transport Effects 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- ULERISLJYQKABB-UHFFFAOYSA-N C1=CC(S(=O)(=O)O)=CC=C1C1=CC2=CC([N]3)=CC=C3C=C(C=C3)NC3=CC([N]3)=CC=C3C=C1N2 Chemical compound C1=CC(S(=O)(=O)O)=CC=C1C1=CC2=CC([N]3)=CC=C3C=C(C=C3)NC3=CC([N]3)=CC=C3C=C1N2 ULERISLJYQKABB-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 239000001116 FEMA 4028 Substances 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000009697 arginine Nutrition 0.000 description 2
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- 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 description 2
- 238000012650 click reaction Methods 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- 239000007923 nasal drop Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 2
- 235000010378 sodium ascorbate Nutrition 0.000 description 2
- 229960005055 sodium ascorbate Drugs 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 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
- 239000004475 Arginine Substances 0.000 description 1
- 229910020366 ClO 4 Inorganic materials 0.000 description 1
- 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 1
- 150000000780 D-glucose derivatives Chemical group 0.000 description 1
- 150000000782 D-glucoses Chemical class 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 101000753769 Homo sapiens Thiamine-triphosphatase Proteins 0.000 description 1
- 241000511976 Hoya Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose 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
- 239000004166 Lanolin Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000004909 Moisturizer Substances 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000012891 Ringer solution Substances 0.000 description 1
- 102100021911 Thiamine-triphosphatase Human genes 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000001484 arginines Chemical class 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 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
- 239000010685 fatty oil Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000010189 intracellular transport Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229910052751 metal Chemical class 0.000 description 1
- 239000002184 metal Chemical class 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 238000012148 non-surgical treatment Methods 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940056211 paraffin Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- MLBYLEUJXUBIJJ-UHFFFAOYSA-N pent-4-ynoic acid Chemical compound OC(=O)CCC#C MLBYLEUJXUBIJJ-UHFFFAOYSA-N 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 238000000954 titration curve Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Description
(1)シクロデキストリン誘導体
この発明のシクロデキストリン誘導体は、下記一般式(1)で表されるシクロデキストリン誘導体である。
この発明のシクロデキストリン誘導体は、公知の方法を組み合わせることによって合成できる。具体的には、例えば、モノアジド化シクロデキストリンとオリゴアルギニンから、Cu(I)触媒アジド-アルキンヒュスゲン反応(クリック反応)によって合成できる。なお、この反応については、文献:Hong, V.; Presolski, S. I.; Ma, C.; Finn, M. G. Angew. Chem. Int. Ed. 2009, 48, 9879-9883に、その詳細が記載されている。
この発明の医薬組成物は、この発明のシクロデキストリン誘導体の疎水性空洞にポルフィリンなどの薬物を包接させた包接錯体を有効成分として含むものである。そこで、その詳細について以下に説明する。
この発明の医薬組成物を構成する薬物は、シクロデキストリン誘導体の疎水性空洞に包接可能な公知の薬物であれば、疾患を特に限定することなく使用できる。中でも、細胞内で効果を生じる薬物が好ましく、難病である癌の治療に使用する薬物がより好ましい。
この発明の医薬組成物の有効成分である包接錯体は、例えば、一般式(1)で表すシクロデキストリン誘導体と、前記一般式(2)又は(3)で表す水溶性金属ポルフィリンとをリン酸緩衝液などの水中で混ぜ合わせることにより製造できる。
この発明の医薬組成物は、種々の形態でヒト又は動物に投与することができ、その投与形態は特に限定されるものではない。具体的には、経口投与でもよいし、静脈内、筋肉内、皮下又は皮内等への注射、直腸内投与、経粘膜投与等の非経口投与でもよい。さらに、埋め込み用ペレットや公知の技術により持続性製剤としてもよい。なお、好ましい投与形態や製剤形態等は、患者の年齢、性別、体質、症状、処置時期等に応じて、医師又は獣医が適宜選択すればよい。
この発明の医薬組成物に含まれる包接錯体の含有量は、投与形態、患者の重篤度や医薬組成物の投与量などによって任意に調整すればよい。
この発明に係るシクロデキストリン誘導体であるオリゴアルギニン修飾シクロデキストリンを図1の合成経路に沿って合成した。なお、理解しやすくするため、以下の説明では、同じ化合物については図1と同じ略称を使用した。
β-CDの第一級水酸基のうちの一つをアジド基で置換したモノアジド化シクロデキストリン、具体的には、mono-6-azido-6-deoxy-β-CD (以下N3-CDと省略する。)及びそのパー-O-メチル化体(以下、N3-CDMeと省略する。)は、前記文献に記載の方法に従って合成した。
アルキンを末端に持つオクタアルギニン(以下、Alkyle-R8と省略する。) は、前記文献に記載の方法に従って合成した。具体的には、以下のようにして合成した。
オクタアルギニン修飾シクロデキストリンは、Alkyne-R8とN3-CD又はN3-CDMeとを、水溶液中でCu(I)触媒アジド-アルキンヒュスゲン反応(クリック反応)により合成した。具体的には、前記文献を参考にして、以下のようにして合成した。
N3-CD(3.5 mg, 3.0 μMol)及びAlkyne-R8 (6.8 mg, 3.0 μMol)を水3 mLに溶解し、 そこに硫酸銅五水和物(0.75 mg, 3.0 μMol)、 リガンド(1,10-フェナントロリン, 1.2 mg, 6.0 μMol)及びアスコルビン酸ナトリウム(1.2 mg, 6.0 μMol)を加え、嫌気下で3時間攪拌した。
N3-CDMe (4.4 mg, 3.0 μMol)及びAlkyne-R8 (13.6 mg, 6.0 μMol)を水3 mLに溶解し、 そこに硫酸銅・五水和物(7.5 mg, 30 μMol)、 リガンド(THTPA, 13.0 mg, 30 μMol、 文献:Hong, V.; Presolski, S. I.; Ma, C.; Finn, M. G. Angew. Chem. Int. Ed. 2009, 48, 9879-9883に従って合成したもの。)、 アミノグアニジン(3.3 mg, 30 μMol)、及びアスコルビン酸ナトリウム(5.9 mg, 30μMol)を加えて、 嫌気下で3時間攪拌した。
シクロデキストリン誘導体である水酸基をメチル基で置換したβ-CD (以下、TMe-β-CDと省略する。)は、水溶液中において5,10,15,20-テトラキス(4-スルホナトフェニル)ポルフィリン(TPPS)を非常に強く包接して2 : 1の包接錯体を形成することが分かっている(文献:Kano, K.; Nishiyabu, R.; Aasada, T.; Kuroda, Y. J. Am. Chem. Soc. 2002, 124, 9937-9944を参照。)。一方、ポルフィリンは、前記のように光線力学療法への利用が注目されている。
R8-CDMeが、水溶液中においてTPPSと包接錯体を形成するかを調べた。具体的には、一定濃度のTPPS (1.6μM)を含むリン酸緩衝液(pH 7.4)に対してR8-CDMeを段階的に加え、その際のUV-visスペクトル変化を25 ℃で測定(UV-2450、SHIMADZU)した。その結果を図7に示す。また、加えたR8-CDMeに対して420 nmにおける吸光度変化をプロットした滴定曲線を図7右上の挿入図に示す。また、同様にして、TPPSを含むリン酸緩衝液に対してTMe-β-CDを段階的に加え、その際のUV-visスペクトル変化を測定した結果を図8に示す。
R8-CDMe/TPPS包接錯体の細胞内移行能を調べた。具体的には、デッシュに付着したHeLa細胞の培養液(OPTI-MEM, Invitrogen, 無血清培地として使用。)に包接錯体(終濃度; [TPPS] = 5μM, [R8-CDMe] = 15μM)を添加し、37 ℃で2時間培養した。その後、培地を新しいものに交換し、顕微鏡(BZ-9000、キーエンス、倍率100倍)を使用して細胞を観測した。また、同濃度のTMe-β-CD/TPPS包接錯体を同様にしてHeLa細胞に添加したのち、顕微鏡を使用して観測した。観測結果を図10に示す。
R8-CDMe及びR8-CDMe/TPPS包接錯体の細胞毒性を調べた。具体的には、(2)細胞内移行能試験と同様に、R8-CDMe、R8-CDMe/TPPS包接錯体を上記と同様の条件でHeLa細胞の培養液に加えて37 ℃で2時間培養した。新しい培地に入れ替えたのち、この新しい培地にカルセイン-AM(DOJINDO)を加えて、生細胞のみを蛍光染色した。これらの細胞を顕微鏡を使用して観測した結果を図11に示す。
R8-CDMe/TPPS包接錯体を細胞に導入したのち、細胞に光照射して光毒性を評価した。具体的には、(2)細胞内移行能試験と同様に、R8-CDMe/TPPS包接錯体をHeLa細胞に添加して、37 ℃で2時間培養した。新しい培地に入れ替えたのち、150 Wキセノンランプ光源から発生しフィルター(B-390、HOYA)を通して310-510 nmの範囲にカットした光を、培地中の細胞に15分間照射した。最後に、培地にカルセイン-AM (DOJINDO)を加えて、生細胞のみを蛍光染色してたのち、蛍光顕微鏡で観察(倍率20倍、励起波長470 ± 20 nm、カルセイン色素が励起される。)した。また、光照射していない対照実験についても同様にして蛍光染色しのち、蛍光顕微鏡で観察した。その結果を図12に示す。
Claims (5)
- 下記一般式(1)で表されるシクロデキストリン誘導体。
- m=8、n=7、Rの全てがCH3である請求項1に記載のシクロデキストリン誘導体。
- ポルフィリンを、請求項1又は請求項2に記載のシクロデキストリン誘導体の疎水性空洞に包接させた包接錯体を有効成分として含む医薬組成物。
- ポルフィリンが、下記一般式(2)又は(3)で表される請求項3に記載の医薬組成物。
- ポルフィリンが、5,10,15,20‐テトラキス(4‐スルホナトフェニル)ポルフィリンである請求項4に記載の医薬組成物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2013178090A JP6180241B2 (ja) | 2013-08-29 | 2013-08-29 | シクロデキストリン誘導体及び医薬組成物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2013178090A JP6180241B2 (ja) | 2013-08-29 | 2013-08-29 | シクロデキストリン誘導体及び医薬組成物 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2015044961A JP2015044961A (ja) | 2015-03-12 |
JP6180241B2 true JP6180241B2 (ja) | 2017-08-16 |
Family
ID=52670739
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2013178090A Active JP6180241B2 (ja) | 2013-08-29 | 2013-08-29 | シクロデキストリン誘導体及び医薬組成物 |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP6180241B2 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20220133692A1 (en) * | 2019-01-31 | 2022-05-05 | Northwestern University | Supramolecular photoprotection of a photosensitizer |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6468777B2 (ja) * | 2014-09-30 | 2019-02-13 | 株式会社リバネス | 改良型葉酸修飾シクロデキストリン誘導体 |
CN117327210B (zh) * | 2023-12-01 | 2024-02-02 | 潍坊医学院 | 一种基于β-环糊精对苯二甲醛包合物的卟啉微孔复合材料及其制备方法和应用 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI321054B (en) * | 2000-12-19 | 2010-03-01 | California Inst Of Techn | Compositions containing inclusion complexes |
JP4870400B2 (ja) * | 2005-08-30 | 2012-02-08 | 公益財団法人野口研究所 | 二本鎖糖分岐シクロデキストリン誘導体 |
EP2194068B1 (en) * | 2007-09-28 | 2013-04-17 | Nanodex INC. | Cyclodextrin compound modified with folic acid, process for production thereof, drug delivery agent for targeting drug delivery system, pharmaceutical composition, and imaging agent |
KR101922752B1 (ko) * | 2011-11-29 | 2018-11-27 | 주록스 피티와이 리미티드 | 사이클로덱스트린 및 소수성 약물을 포함하는 주사용 약제학적 조성물을 보존하는 방법 |
-
2013
- 2013-08-29 JP JP2013178090A patent/JP6180241B2/ja active Active
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20220133692A1 (en) * | 2019-01-31 | 2022-05-05 | Northwestern University | Supramolecular photoprotection of a photosensitizer |
Also Published As
Publication number | Publication date |
---|---|
JP2015044961A (ja) | 2015-03-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Peng et al. | Carbon dots: biomacromolecule interaction, bioimaging and nanomedicine | |
Meng et al. | Synthesis, characterization and in vitro photodynamic antimicrobial activity of basic amino acid–porphyrin conjugates | |
Zhang et al. | Smart Cu (II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable intracellular prodrug release, photodynamic treatment and aggregation induced photothermal therapy of hepatocellular carcinoma | |
Liu et al. | Synthesis and cellular studies of nonaggregated water-soluble phthalocyanines | |
US20080004345A1 (en) | Novel Water-Soluble Fullerene, Process for Producing the Same and Active Oxygen Generator Containing the Fullerene | |
Li et al. | Size-tunable targeting-triggered nanophotosensitizers based on self-assembly of a phthalocyanine–biotin conjugate for photodynamic therapy | |
Wang et al. | Tumor‐microenvironment‐activated in situ self‐assembly of sequentially responsive biopolymer for targeted photodynamic therapy | |
Tan et al. | Spider toxin peptide lycosin-I functionalized gold nanoparticles for in vivo tumor targeting and therapy | |
Metzler-Nolte | Medicinal applications of metal–peptide bioconjugates | |
KR101419124B1 (ko) | 폴리에틸렌옥사이드-폴리프로필렌옥사이드 블록공중합체와 광감작제가 공유 결합된 광역학 치료용 복합체 | |
Zhang et al. | Mitochondrial voltage-dependent anion channel 1–hexokinase-II complex-targeted strategy for melanoma inhibition using designed multiblock peptide amphiphiles | |
Serda et al. | Development of photoactive Sweet-C60 for pancreatic cancer stellate cell therapy | |
WO2010098442A1 (ja) | 一酸化炭素除去剤 | |
Zhou et al. | Development of organic photosensitizers for antimicrobial photodynamic therapy | |
JP6180241B2 (ja) | シクロデキストリン誘導体及び医薬組成物 | |
Mavridis et al. | Porphyrinoid–Cyclodextrin assemblies in biomedical research: an update | |
Lv et al. | Review of lipoic acid: from a clinical therapeutic agent to various emerging biomaterials | |
US20220071918A1 (en) | Mussel adhesive protein-based photothermal agent and photothermal- responsive adhesive nanoparticles | |
Liu et al. | Lighting up individual organelles with fluorescent carbon dots | |
CN111848658A (zh) | 一种靶向线粒体的氟硼二吡咯类化合物及其脂质体包裹纳米粒子的制备方法和用途 | |
Tam et al. | A Tumor‐Targeting Dual‐Stimuli‐Activatable Photodynamic Molecular Beacon for Precise Photodynamic Therapy | |
WO2012028874A1 (en) | Cytotoxic luminescent metal complexes | |
Ghosh et al. | Self-assembled porphyrin–peptide cages for photodynamic therapy | |
Shi et al. | Multiscale Bioresponses of Metal Nanoclusters | |
JP5807927B2 (ja) | 内表面疎水化有機ナノチューブ、および同ナノチューブを用いた薬剤カプセル化物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20160706 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170523 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170601 |
|
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: 20170627 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20170718 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6180241 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 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |