JPH02203A - Drug carrier - Google Patents
Drug carrierInfo
- Publication number
- JPH02203A JPH02203A JP63249526A JP24952688A JPH02203A JP H02203 A JPH02203 A JP H02203A JP 63249526 A JP63249526 A JP 63249526A JP 24952688 A JP24952688 A JP 24952688A JP H02203 A JPH02203 A JP H02203A
- Authority
- JP
- Japan
- Prior art keywords
- drug
- drug carrier
- lipid
- sample
- mixture
- 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.)
- Granted
Links
- 239000003937 drug carrier Substances 0.000 title claims abstract description 108
- 239000003814 drug Substances 0.000 claims abstract description 91
- 229940079593 drug Drugs 0.000 claims abstract description 89
- 239000002245 particle Substances 0.000 claims abstract description 59
- 150000002632 lipids Chemical class 0.000 claims abstract description 47
- -1 sterol ester Chemical class 0.000 claims abstract description 24
- 239000002960 lipid emulsion Substances 0.000 claims abstract description 22
- 239000000126 substance Substances 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 20
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 7
- 239000002344 surface layer Substances 0.000 claims abstract description 7
- 229930186217 Glycolipid Natural products 0.000 claims abstract description 4
- 230000007935 neutral effect Effects 0.000 claims abstract description 4
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 claims abstract 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 10
- 239000000194 fatty acid Substances 0.000 claims description 10
- 229930195729 fatty acid Natural products 0.000 claims description 10
- 150000004665 fatty acids Chemical class 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000693 micelle Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims 1
- 239000006185 dispersion Substances 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- 239000008280 blood Substances 0.000 abstract description 14
- 210000004369 blood Anatomy 0.000 abstract description 14
- 238000012546 transfer Methods 0.000 abstract description 9
- 239000011882 ultra-fine particle Substances 0.000 abstract description 6
- 230000000144 pharmacologic effect Effects 0.000 abstract description 5
- 229930182558 Sterol Natural products 0.000 abstract description 4
- 235000003702 sterols Nutrition 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 3
- 239000000523 sample Substances 0.000 description 61
- 238000012360 testing method Methods 0.000 description 56
- 239000013068 control sample Substances 0.000 description 44
- FWKQNCXZGNBPFD-UHFFFAOYSA-N Guaiazulene Chemical compound CC(C)C1=CC=C(C)C2=CC=C(C)C2=C1 FWKQNCXZGNBPFD-UHFFFAOYSA-N 0.000 description 24
- 230000000694 effects Effects 0.000 description 22
- 210000001519 tissue Anatomy 0.000 description 20
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 17
- 241000700159 Rattus Species 0.000 description 15
- 238000000149 argon plasma sintering Methods 0.000 description 14
- 239000000679 carrageenan Substances 0.000 description 13
- 229920001525 carrageenan Polymers 0.000 description 13
- 229940113118 carrageenan Drugs 0.000 description 13
- 239000012528 membrane Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 12
- 229960002350 guaiazulen Drugs 0.000 description 12
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 12
- 210000004379 membrane Anatomy 0.000 description 12
- 239000003549 soybean oil Substances 0.000 description 11
- 235000012424 soybean oil Nutrition 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000013508 migration Methods 0.000 description 10
- 230000005012 migration Effects 0.000 description 10
- 230000008728 vascular permeability Effects 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 9
- 235000010418 carrageenan Nutrition 0.000 description 9
- 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 9
- 235000011187 glycerol Nutrition 0.000 description 9
- 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 9
- 238000000034 method Methods 0.000 description 8
- 210000003462 vein Anatomy 0.000 description 8
- 206010030113 Oedema Diseases 0.000 description 7
- BAECOWNUKCLBPZ-HIUWNOOHSA-N Triolein Natural products O([C@H](OCC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC BAECOWNUKCLBPZ-HIUWNOOHSA-N 0.000 description 7
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 description 7
- 230000003902 lesion Effects 0.000 description 7
- 239000002502 liposome Substances 0.000 description 7
- 239000002504 physiological saline solution Substances 0.000 description 7
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 7
- 229940117972 triolein Drugs 0.000 description 7
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 210000001508 eye Anatomy 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 239000002260 anti-inflammatory agent Substances 0.000 description 5
- 210000004204 blood vessel Anatomy 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 239000000470 constituent Substances 0.000 description 5
- 229960000520 diphenhydramine Drugs 0.000 description 5
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000010452 phosphate Substances 0.000 description 5
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 102000002322 Egg Proteins Human genes 0.000 description 4
- 108010000912 Egg Proteins Proteins 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 210000005252 bulbus oculi Anatomy 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 235000013345 egg yolk Nutrition 0.000 description 4
- 210000002969 egg yolk Anatomy 0.000 description 4
- 229960003699 evans blue Drugs 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 210000001165 lymph node Anatomy 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000009210 therapy by ultrasound Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000002253 acid Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 210000004100 adrenal gland Anatomy 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 description 3
- 239000000739 antihistaminic agent Substances 0.000 description 3
- 210000001742 aqueous humor Anatomy 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 229960000684 cytarabine Drugs 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229960004857 mitomycin Drugs 0.000 description 3
- 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 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 150000003432 sterols Chemical class 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 238000002525 ultrasonication Methods 0.000 description 3
- 229960003048 vinblastine Drugs 0.000 description 3
- 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 3
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 2
- NGSWKAQJJWESNS-UHFFFAOYSA-N 4-coumaric acid Chemical compound OC(=O)C=CC1=CC=C(O)C=C1 NGSWKAQJJWESNS-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-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
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 2
- 206010018691 Granuloma Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000000232 Lipid Bilayer Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- RJECHNNFRHZQKU-UHFFFAOYSA-N Oelsaeurecholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCC=CCCCCCCCC)C2 RJECHNNFRHZQKU-UHFFFAOYSA-N 0.000 description 2
- 235000008753 Papaver somniferum Nutrition 0.000 description 2
- 240000001090 Papaver somniferum Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 2
- SJDMTGSQPOFVLR-UHFFFAOYSA-N [10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] tetradecanoate Chemical compound C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCCCCCCC)C2 SJDMTGSQPOFVLR-UHFFFAOYSA-N 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000003699 antiulcer agent Substances 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 210000000702 aorta abdominal Anatomy 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- 229940124630 bronchodilator Drugs 0.000 description 2
- 239000000168 bronchodilator agent Substances 0.000 description 2
- CRPUJAZIXJMDBK-UHFFFAOYSA-N camphene Chemical class C1CC2C(=C)C(C)(C)C1C2 CRPUJAZIXJMDBK-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- RJECHNNFRHZQKU-RMUVNZEASA-N cholesteryl oleate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)C1 RJECHNNFRHZQKU-RMUVNZEASA-N 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 238000002485 combustion reaction Methods 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 239000000032 diagnostic agent Substances 0.000 description 2
- 229940039227 diagnostic agent Drugs 0.000 description 2
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 description 2
- 238000009513 drug distribution Methods 0.000 description 2
- 230000002497 edematous effect Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 229960003720 enoxolone Drugs 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- RRAFCDWBNXTKKO-UHFFFAOYSA-N eugenol Chemical class COC1=CC(CC=C)=CC=C1O RRAFCDWBNXTKKO-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- QBKSWRVVCFFDOT-UHFFFAOYSA-N gossypol Chemical compound CC(C)C1=C(O)C(O)=C(C=O)C2=C(O)C(C=3C(O)=C4C(C=O)=C(O)C(O)=C(C4=CC=3C)C(C)C)=C(C)C=C21 QBKSWRVVCFFDOT-UHFFFAOYSA-N 0.000 description 2
- 150000000467 guaiazulene derivatives Chemical class 0.000 description 2
- 241000411851 herbal medicine Species 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 229960005015 local anesthetics Drugs 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 210000004224 pleura Anatomy 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- GEYJUFBPCGDENK-UHFFFAOYSA-M sodium;3,8-dimethyl-5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=C(C)C2=C(S([O-])(=O)=O)C=C(C)C2=C1 GEYJUFBPCGDENK-UHFFFAOYSA-M 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- DUXYWXYOBMKGIN-UHFFFAOYSA-N trimyristin Chemical compound CCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCC DUXYWXYOBMKGIN-UHFFFAOYSA-N 0.000 description 2
- PVNIQBQSYATKKL-UHFFFAOYSA-N tripalmitin Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC PVNIQBQSYATKKL-UHFFFAOYSA-N 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 239000003021 water soluble solvent Substances 0.000 description 2
- SLRCCWJSBJZJBV-LXTVHRRPSA-N (-)-Spartein Natural products C1N2CCCC[C@@H]2[C@H]2CN3CCCC[C@@H]3[C@H]1C2 SLRCCWJSBJZJBV-LXTVHRRPSA-N 0.000 description 1
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 1
- FMCGSUUBYTWNDP-ONGXEEELSA-N (1R,2S)-2-(dimethylamino)-1-phenyl-1-propanol Chemical compound CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-ONGXEEELSA-N 0.000 description 1
- CRDAMVZIKSXKFV-FBXUGWQNSA-N (2-cis,6-cis)-farnesol Chemical compound CC(C)=CCC\C(C)=C/CC\C(C)=C/CO CRDAMVZIKSXKFV-FBXUGWQNSA-N 0.000 description 1
- LJPQBEUXEDLQEJ-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl) 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetate Chemical compound C12=CC=C(OC)C=C2C(CC(=O)OCC(=O)OCC)=C(C)N1C(=O)C1=CC=C(Cl)C=C1 LJPQBEUXEDLQEJ-UHFFFAOYSA-N 0.000 description 1
- 239000000260 (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol Substances 0.000 description 1
- WJHFZYAELPOJIV-IJFRVEDASA-N (2E,6E)-farnesoic acid Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\C(O)=O WJHFZYAELPOJIV-IJFRVEDASA-N 0.000 description 1
- DJAHKBBSJCDSOZ-AJLBTXRUSA-N (5z,9e,13e)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one;(5e,9e,13e)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C/CCC(C)=O.CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C\CCC(C)=O DJAHKBBSJCDSOZ-AJLBTXRUSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- OTVRYZXVVMZHHW-FNOPAARDSA-N (8s,9s,10r,13r,14s,17r)-3-chloro-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthrene Chemical compound C1C=C2CC(Cl)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 OTVRYZXVVMZHHW-FNOPAARDSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- 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 1
- 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 1
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-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
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 1
- 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 1
- OZOMQRBLCMDCEG-CHHVJCJISA-N 1-[(z)-[5-(4-nitrophenyl)furan-2-yl]methylideneamino]imidazolidine-2,4-dione Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N/N1C(=O)NC(=O)C1 OZOMQRBLCMDCEG-CHHVJCJISA-N 0.000 description 1
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-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
- YNJFYAVGJCAZGH-UHFFFAOYSA-N 2,3-dichloro-2-phenyl-3,4-dihydrochromene Chemical compound ClC1CC2=CC=CC=C2OC1(Cl)C1=CC=CC=C1 YNJFYAVGJCAZGH-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- YMXMDERILJQYMS-UHFFFAOYSA-N 2-(2-phenylphenyl)propanoic acid Chemical class OC(=O)C(C)C1=CC=CC=C1C1=CC=CC=C1 YMXMDERILJQYMS-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- VADKRMSMGWJZCF-UHFFFAOYSA-N 2-bromophenol Chemical compound OC1=CC=CC=C1Br VADKRMSMGWJZCF-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- NGSWKAQJJWESNS-ZZXKWVIFSA-M 4-Hydroxycinnamate Natural products OC1=CC=C(\C=C\C([O-])=O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-M 0.000 description 1
- DAGTYOAEYKEZLK-UHFFFAOYSA-N 5-fluoro-1h-pyrimidine-2,4-dione;hexadecanoic acid Chemical compound FC1=CNC(=O)NC1=O.CCCCCCCCCCCCCCCC(O)=O DAGTYOAEYKEZLK-UHFFFAOYSA-N 0.000 description 1
- WDQCVSKYDPYZKV-UHFFFAOYSA-N 5-fluoro-1h-pyrimidine-2,4-dione;tetradecanoic acid Chemical compound FC1=CNC(=O)NC1=O.CCCCCCCCCCCCCC(O)=O WDQCVSKYDPYZKV-UHFFFAOYSA-N 0.000 description 1
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- DFYRUELUNQRZTB-UHFFFAOYSA-N Acetovanillone Natural products COC1=CC(C(C)=O)=CC=C1O DFYRUELUNQRZTB-UHFFFAOYSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N Aminoantipyrine Natural products CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 1
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 1
- 229930183010 Amphotericin Natural products 0.000 description 1
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102000007592 Apolipoproteins Human genes 0.000 description 1
- 108010071619 Apolipoproteins Proteins 0.000 description 1
- 101100005765 Arabidopsis thaliana CDF1 gene Proteins 0.000 description 1
- 101100007579 Arabidopsis thaliana CPP1 gene Proteins 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 240000002791 Brassica napus Species 0.000 description 1
- 235000004977 Brassica sinapistrum Nutrition 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- 244000020518 Carthamus tinctorius Species 0.000 description 1
- 235000003255 Carthamus tinctorius Nutrition 0.000 description 1
- NPBVQXIMTZKSBA-UHFFFAOYSA-N Chavibetol Chemical class COC1=CC=C(CC=C)C=C1O NPBVQXIMTZKSBA-UHFFFAOYSA-N 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 description 1
- CHBRHODLKOZEPZ-UHFFFAOYSA-N Clotiazepam Chemical compound S1C(CC)=CC2=C1N(C)C(=O)CN=C2C1=CC=CC=C1Cl CHBRHODLKOZEPZ-UHFFFAOYSA-N 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical group O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- QFVAWNPSRQWSDU-UHFFFAOYSA-N Dibenzthion Chemical compound C1N(CC=2C=CC=CC=2)C(=S)SCN1CC1=CC=CC=C1 QFVAWNPSRQWSDU-UHFFFAOYSA-N 0.000 description 1
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- 239000004129 EU approved improving agent Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- WEEGYLXZBRQIMU-UHFFFAOYSA-N Eucalyptol Chemical class C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 description 1
- 239000005770 Eugenol Chemical class 0.000 description 1
- 239000001293 FEMA 3089 Substances 0.000 description 1
- ZGIGZINMAOQWLX-UHFFFAOYSA-N Farnesyl acetate Natural products CC(C)=CCCC(C)=CCCC(C)=CCOC(C)=O ZGIGZINMAOQWLX-UHFFFAOYSA-N 0.000 description 1
- ZPACYDRSPFRDHO-ROBAGEODSA-N Gefarnate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CCC(=O)OC\C=C(/C)CCC=C(C)C ZPACYDRSPFRDHO-ROBAGEODSA-N 0.000 description 1
- 229920001386 Gefarnate Polymers 0.000 description 1
- 239000005792 Geraniol Substances 0.000 description 1
- GLZPCOQZEFWAFX-YFHOEESVSA-N Geraniol Natural products CC(C)=CCC\C(C)=C/CO GLZPCOQZEFWAFX-YFHOEESVSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 241000219146 Gossypium Species 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- YLCXGBZIZBEVPZ-UHFFFAOYSA-N Medazepam Chemical compound C12=CC(Cl)=CC=C2N(C)CCN=C1C1=CC=CC=C1 YLCXGBZIZBEVPZ-UHFFFAOYSA-N 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- PQMWYJDJHJQZDE-UHFFFAOYSA-M Methantheline bromide Chemical compound [Br-].C1=CC=C2C(C(=O)OCC[N+](C)(CC)CC)C3=CC=CC=C3OC2=C1 PQMWYJDJHJQZDE-UHFFFAOYSA-M 0.000 description 1
- JEYCTXHKTXCGPB-UHFFFAOYSA-N Methaqualone Chemical compound CC1=CC=CC=C1N1C(=O)C2=CC=CC=C2N=C1C JEYCTXHKTXCGPB-UHFFFAOYSA-N 0.000 description 1
- UEQUQVLFIPOEMF-UHFFFAOYSA-N Mianserin Chemical compound C1C2=CC=CC=C2N2CCN(C)CC2C2=CC=CC=C21 UEQUQVLFIPOEMF-UHFFFAOYSA-N 0.000 description 1
- DMUAPQTXSSNEDD-QALJCMCCSA-N Midecamycin Chemical compound C1[C@](O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C DMUAPQTXSSNEDD-QALJCMCCSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- FMCGSUUBYTWNDP-UHFFFAOYSA-N N-Methylephedrine Natural products CN(C)C(C)C(O)C1=CC=CC=C1 FMCGSUUBYTWNDP-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- DUDKAZCAISNGQN-UHFFFAOYSA-N Oxyphencyclimine Chemical compound CN1CCCN=C1COC(=O)C(O)(C=1C=CC=CC=1)C1CCCCC1 DUDKAZCAISNGQN-UHFFFAOYSA-N 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- BBJQPKLGPMQWBU-UHFFFAOYSA-N Palmitinsaeurecholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCCCCCCCCC)C2 BBJQPKLGPMQWBU-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- QZVCTJOXCFMACW-UHFFFAOYSA-N Phenoxybenzamine Chemical compound C=1C=CC=CC=1CN(CCCl)C(C)COC1=CC=CC=C1 QZVCTJOXCFMACW-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- PXRCIOIWVGAZEP-UHFFFAOYSA-N Primaeres Camphenhydrat Chemical class C1CC2C(O)(C)C(C)(C)C1C2 PXRCIOIWVGAZEP-UHFFFAOYSA-N 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- UVMRYBDEERADNV-UHFFFAOYSA-N Pseudoeugenol Chemical class COC1=CC(C(C)=C)=CC=C1O UVMRYBDEERADNV-UHFFFAOYSA-N 0.000 description 1
- 235000019484 Rapeseed oil Nutrition 0.000 description 1
- CEEMRWKKNNEQDT-UHFFFAOYSA-N Rosmanol Chemical class CC(C)c1cc2C(OC(=O)C)C3OC(=O)C4(CCCC(C)(C)C34)c2c(OC(=O)C)c1OC(=O)C CEEMRWKKNNEQDT-UHFFFAOYSA-N 0.000 description 1
- SMTZFNFIKUPEJC-UHFFFAOYSA-N Roxane Chemical compound CC(=O)OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 SMTZFNFIKUPEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- QHOPXUFELLHKAS-UHFFFAOYSA-N Thespesin Natural products CC(C)c1c(O)c(O)c2C(O)Oc3c(c(C)cc1c23)-c1c2OC(O)c3c(O)c(O)c(C(C)C)c(cc1C)c23 QHOPXUFELLHKAS-UHFFFAOYSA-N 0.000 description 1
- RUJBDQSFYCKFAA-UHFFFAOYSA-N Tofisopam Chemical compound N=1N=C(C)C(CC)C2=CC(OC)=C(OC)C=C2C=1C1=CC=C(OC)C(OC)=C1 RUJBDQSFYCKFAA-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- JSZILQVIPPROJI-CEXWTWQISA-N [(2R,3R,11bS)-3-(diethylcarbamoyl)-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-yl] acetate Chemical compound C1CC2=CC(OC)=C(OC)C=C2[C@H]2N1C[C@@H](C(=O)N(CC)CC)[C@H](OC(C)=O)C2 JSZILQVIPPROJI-CEXWTWQISA-N 0.000 description 1
- JLPULHDHAOZNQI-JLOPVYAASA-N [(2r)-3-hexadecanoyloxy-2-[(9e,12e)-octadeca-9,12-dienoyl]oxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC JLPULHDHAOZNQI-JLOPVYAASA-N 0.000 description 1
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 1
- AVTXVDFKYBVTKR-DPAQBDIFSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] dihydrogen phosphate Chemical compound C1C=C2C[C@@H](OP(O)(O)=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 AVTXVDFKYBVTKR-DPAQBDIFSA-N 0.000 description 1
- SUOVMGLZSOAHJY-JREUTYQLSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] icosanoate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCCCCCCCCCCCCCC)C1 SUOVMGLZSOAHJY-JREUTYQLSA-N 0.000 description 1
- YNVPFGZVMSQKIC-CUUJIVLRSA-N [2-[(8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] hexadecanoate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CCCCCCCCCCCCCCC)(O)[C@@]1(C)C[C@@H]2O YNVPFGZVMSQKIC-CUUJIVLRSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000003677 abuse test Methods 0.000 description 1
- 229960004871 acetoxolone Drugs 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- XCPQUQHBVVXMRQ-UHFFFAOYSA-N alpha-Fenchene Chemical class C1CC2C(=C)CC1C2(C)C XCPQUQHBVVXMRQ-UHFFFAOYSA-N 0.000 description 1
- SLRCCWJSBJZJBV-UHFFFAOYSA-N alpha-isosparteine Natural products C1N2CCCCC2C2CN3CCCCC3C1C2 SLRCCWJSBJZJBV-UHFFFAOYSA-N 0.000 description 1
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960000212 aminophenazone Drugs 0.000 description 1
- 229940009444 amphotericin Drugs 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 1
- 229950000242 ancitabine Drugs 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000002402 anti-lipaemic effect Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- VEQOALNAAJBPNY-UHFFFAOYSA-N antipyrine Chemical compound CN1C(C)=CC(=O)N1C1=CC=CC=C1 VEQOALNAAJBPNY-UHFFFAOYSA-N 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 210000000544 articulatio talocruralis Anatomy 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 229960004574 azelastine Drugs 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229960001081 benzatropine Drugs 0.000 description 1
- GIJXKZJWITVLHI-PMOLBWCYSA-N benzatropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(C=1C=CC=CC=1)C1=CC=CC=C1 GIJXKZJWITVLHI-PMOLBWCYSA-N 0.000 description 1
- 229960005274 benzocaine Drugs 0.000 description 1
- 229960004564 benzquinamide Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- QXMNTPFFZFYQAI-IMDKZJJXSA-N beta-sitosterol 3-O-beta-D-glucopyranoside Natural products CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@H](CC[C@]4(C)[C@H]3CC[C@]12C)O[C@@H]5C[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)C(C)C QXMNTPFFZFYQAI-IMDKZJJXSA-N 0.000 description 1
- QHKKPRDTANXCBJ-UHFFFAOYSA-N beta-sitosterol-delta-glucopyranoside Natural products CCC(CCC(C)C1CCC2C3CC=C4CC(CCC4(C)C3CCC12C)OC5OC(OC)C(O)C(O)C5O)C(C)C QHKKPRDTANXCBJ-UHFFFAOYSA-N 0.000 description 1
- YCHQFVUAIVWDNL-UHFFFAOYSA-N beta-sitosteryl-beta-D-glucoside Natural products CCC(CCC(C)C1CCC2C3CC=C4CC(CCC4(C)C3CCC2(C)C1)OC5OC(CO)C(O)C(O)C5O)C(C)C YCHQFVUAIVWDNL-UHFFFAOYSA-N 0.000 description 1
- 239000003012 bilayer membrane Substances 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000010495 camellia oil Substances 0.000 description 1
- 229930006739 camphene Chemical class 0.000 description 1
- ZYPYEBYNXWUCEA-UHFFFAOYSA-N camphenilone Chemical class C1CC2C(=O)C(C)(C)C1C2 ZYPYEBYNXWUCEA-UHFFFAOYSA-N 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001765 catechin Chemical class 0.000 description 1
- ADRVNXBAWSRFAJ-UHFFFAOYSA-N catechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3ccc(O)c(O)c3 ADRVNXBAWSRFAJ-UHFFFAOYSA-N 0.000 description 1
- 235000005487 catechin Nutrition 0.000 description 1
- 239000003576 central nervous system agent Substances 0.000 description 1
- 229940125693 central nervous system agent Drugs 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000012829 chemotherapy agent Substances 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- BBJQPKLGPMQWBU-JADYGXMDSA-N cholesteryl palmitate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCCCCCCCCCC)C1 BBJQPKLGPMQWBU-JADYGXMDSA-N 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- RFFOTVCVTJUTAD-UHFFFAOYSA-N cineole Chemical class C1CC2(C)CCC1(C(C)C)O2 RFFOTVCVTJUTAD-UHFFFAOYSA-N 0.000 description 1
- 229960005233 cineole Drugs 0.000 description 1
- DERZBLKQOCDDDZ-JLHYYAGUSA-N cinnarizine Chemical compound C1CN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)CCN1C\C=C\C1=CC=CC=C1 DERZBLKQOCDDDZ-JLHYYAGUSA-N 0.000 description 1
- 229960000876 cinnarizine Drugs 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- 229960004606 clomipramine Drugs 0.000 description 1
- 229960003622 clotiazepam Drugs 0.000 description 1
- 239000010634 clove oil Substances 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 229960001987 dantrolene Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229960002069 diamorphine Drugs 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- RNPXCFINMKSQPQ-UHFFFAOYSA-N dicetyl hydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCCCC RNPXCFINMKSQPQ-UHFFFAOYSA-N 0.000 description 1
- 229940093541 dicetylphosphate Drugs 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- HZTMGWSBSDLALI-UHFFFAOYSA-N dimorpholamine Chemical compound C1COCCN1C(=O)N(CCCC)CCN(CCCC)C(=O)N1CCOCC1 HZTMGWSBSDLALI-UHFFFAOYSA-N 0.000 description 1
- 229950003539 dimorpholamine Drugs 0.000 description 1
- OGAKLTJNUQRZJU-UHFFFAOYSA-N diphenidol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)CCCN1CCCCC1 OGAKLTJNUQRZJU-UHFFFAOYSA-N 0.000 description 1
- 229960003520 diphenidol Drugs 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 229960002217 eugenol Drugs 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 229940043259 farnesol Drugs 0.000 description 1
- 229930002886 farnesol Natural products 0.000 description 1
- 229940007703 farnesyl acetate Drugs 0.000 description 1
- 239000010643 fennel seed oil Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 150000002212 flavone derivatives Chemical class 0.000 description 1
- SPIUTQOUKAMGCX-UHFFFAOYSA-N flavoxate Chemical compound C1=CC=C2C(=O)C(C)=C(C=3C=CC=CC=3)OC2=C1C(=O)OCCN1CCCCC1 SPIUTQOUKAMGCX-UHFFFAOYSA-N 0.000 description 1
- 229960000855 flavoxate Drugs 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- 229960001347 fluocinolone acetonide Drugs 0.000 description 1
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 210000004744 fore-foot Anatomy 0.000 description 1
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical class OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 1
- 229960003779 gefarnate Drugs 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 229940113087 geraniol Drugs 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 229930000755 gossypol Natural products 0.000 description 1
- 229950005277 gossypol Drugs 0.000 description 1
- 230000033687 granuloma formation Effects 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 1
- 229960000645 histamine hydrochloride Drugs 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- JOOXCMJARBKPKM-UHFFFAOYSA-N laevulinic acid Natural products CC(=O)CCC(O)=O JOOXCMJARBKPKM-UHFFFAOYSA-N 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229940040102 levulinic acid Drugs 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 229930013686 lignan Chemical class 0.000 description 1
- 235000009408 lignans Nutrition 0.000 description 1
- 150000005692 lignans Chemical class 0.000 description 1
- 235000001510 limonene Nutrition 0.000 description 1
- 229940087305 limonene Drugs 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960002225 medazepam Drugs 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229960005042 mequitazine Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229960002803 methaqualone Drugs 0.000 description 1
- 229960002221 methylephedrine Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960003955 mianserin Drugs 0.000 description 1
- 229960002757 midecamycin Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229960000210 nalidixic acid Drugs 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 230000000683 nonmetastatic effect Effects 0.000 description 1
- 229960004708 noscapine Drugs 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 229960002369 oxyphencyclimine Drugs 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960005222 phenazone Drugs 0.000 description 1
- 229960003418 phenoxybenzamine Drugs 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- 229960004633 pirenzepine Drugs 0.000 description 1
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- SUWYPNNPLSRNPS-UNTSEYQFSA-N plaunotol Chemical compound CC(C)=CCC\C(C)=C\CC\C(CO)=C\CC\C(C)=C\CO SUWYPNNPLSRNPS-UNTSEYQFSA-N 0.000 description 1
- 229950009291 plaunotol Drugs 0.000 description 1
- SUWYPNNPLSRNPS-UHFFFAOYSA-N plaunotol Natural products CC(C)=CCCC(C)=CCCC(CO)=CCCC(C)=CCO SUWYPNNPLSRNPS-UHFFFAOYSA-N 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- WIKYUJGCLQQFNW-UHFFFAOYSA-N prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 description 1
- 229960003111 prochlorperazine Drugs 0.000 description 1
- 150000003151 propanoic acid esters Chemical class 0.000 description 1
- 150000003163 prostaglandin D2 derivatives Chemical class 0.000 description 1
- 150000003165 prostaglandin E1 derivatives Chemical class 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 230000003307 reticuloendothelial effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- LCAZOMIGFDQMNC-FORWCCJISA-N rosmanol Chemical class C1CCC(C)(C)[C@@H]2[C@H]3[C@@H](O)C(C=C(C(=C4O)O)C(C)C)=C4[C@]21C(=O)O3 LCAZOMIGFDQMNC-FORWCCJISA-N 0.000 description 1
- 229960003287 roxatidine acetate Drugs 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 239000010670 sage oil Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- SLRCCWJSBJZJBV-AJNGGQMLSA-N sparteine Chemical compound C1N2CCCC[C@H]2[C@@H]2CN3CCCC[C@H]3[C@H]1C2 SLRCCWJSBJZJBV-AJNGGQMLSA-N 0.000 description 1
- 229960001945 sparteine Drugs 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960002999 sulbentine Drugs 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 229950006156 teprenone Drugs 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 229960002372 tetracaine Drugs 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical class O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 239000010678 thyme oil Substances 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 125000002640 tocopherol group Chemical class 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 229960002501 tofisopam Drugs 0.000 description 1
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 1
- 229960005342 tranilast Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- CRDAMVZIKSXKFV-UHFFFAOYSA-N trans-Farnesol Natural products CC(C)=CCCC(C)=CCCC(C)=CCO CRDAMVZIKSXKFV-UHFFFAOYSA-N 0.000 description 1
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical class OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 description 1
- IRYJRGCIQBGHIV-UHFFFAOYSA-N trimethadione Chemical compound CN1C(=O)OC(C)(C)C1=O IRYJRGCIQBGHIV-UHFFFAOYSA-N 0.000 description 1
- 229960004453 trimethadione Drugs 0.000 description 1
- 229940113164 trimyristin Drugs 0.000 description 1
- 229960001947 tripalmitin Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229960004747 ubidecarenone Drugs 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229960001722 verapamil 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
- 229960004528 vincristine Drugs 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
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
本発明は1.その中に含有する薬物の血液中又は通用部
位から病変組織への移行性を改善するために改良された
薬物担体に関する。The present invention consists of 1. The present invention relates to a drug carrier that has been improved in order to improve the migration of the drug contained therein into the blood or from a common site to a diseased tissue.
含有する薬物の血液中又は適用部位から病変組織への移
行性を改善するための薬物担体に関する研究は、これま
で種々行われてきていた。例えば、リン脂質で調製した
リポソームに薬物を包含させて利用する方法がある(
rDrug Carriers inBiology
and MedicineJ (1979) +
Ed、 bV G。
Gregoriadis、 Academic Pre
ss ) 。
しかしながら、この方法では、■水層を脂質二重層で包
含するリポソームには保存時の安定性に問題が多いこと
、■血液中に投与した場合に、はとんどが肝臓及び肺臓
等のIB細網内皮系RES)の発達した組織に取り込ま
れてその他の細胞や組織に分配されにくいこと、等の欠
点を有していた。
これは、リポソームがリン脂質二分子膜によって内外の
水層を隔てる構造を有しているため種々の力に対して安
定ではないためであると考えられ、凝集による粒子径の
増大も又、保存時の欠点として知られていた。
近年の研究によれば、従来より高カロリー輸液として栄
養補給のために臨床的に用いられている大豆油と卵黄レ
シチンからなる粒子径0.2μmの脂肪乳剤に種々の薬
物を溶解して用いる技術があり、上記目的のために良好
な結果をえている(最新医学。40.1806〜181
3 (1980) ’)。このものをよ、内部に水層を
持たずリポソームに比べて極めて安定に保存することが
できる特徴を有している。
しかしながら、このものは、上述した肝臓等の細彫岡内
皮系に速やかに取り込まれる性質を有している。このよ
うに代謝が速やかであることは、高カロリー輸液として
は望ましいものであっても、上記目的に通う薬物担体と
しては、他の組織への薬物の分配が低くなることなどの
問題点を有し、必ずしも望ましいものではなかった。
また公表特許公報(特表昭63−500456号公報)
において、90%が100±30nmの脂肪乳剤を薬物
の担体とする技術が知られている。このものもその特徴
として肝臓や肺臓等の細網内皮系への集積性を有するも
のであり、前述のごとく他の組織への薬物分配に問題点
を有していた。
上記の問題点を解決する手段として、単純脂質(ステロ
ール類を含む。本明細書において同じ)、複合脂質、及
びアポリボ蛋白からなる血清リボ蛋白を薬物担体として
応用する技術が知られていた(特開昭60−16382
4号公報)。しかしながら、このものは、リポ蛋白の生
理的で特異的な認識能により薬物を細胞へ導くものであ
るからレセプターを介して速やかに組織へ移行するため
に、血中からの消失が比較的速やかであり、そのために
レセプター活性の低い組織への移行は必ずしも充分では
なく、またアポリポ蛋白がその構成成分として不可欠な
ため製造コストが高くなるという工業技術上の欠点を有
していた。
更に粒子径200nmの脂肪乳剤を更に微細化する試み
(特開昭62−029511号公報)が知られるが、こ
のものは用いる卵黄レシチンが少ないため生成する微細
粒子が時間とともに再凝集するため、安定性に問題を有
していた。また、生体内での安定性にも欠点を有し、他
の組織への移行性に関して望ましいものではなかった。Various studies have been conducted on drug carriers for improving the migration of drugs contained in the blood or from the application site to diseased tissue. For example, there is a method of incorporating drugs into liposomes prepared with phospholipids (
rDrug Carriers in Biology
and MedicineJ (1979) +
Ed, bVG. Gregoriadis, Academic Pre
ss). However, with this method, 1) liposomes containing an aqueous layer with a lipid bilayer have many problems with stability during storage, and 2) when administered into the blood, most of the It has drawbacks such as being taken up into tissues with developed reticuloendothelial system (RES) and difficult to be distributed to other cells and tissues. This is thought to be because liposomes have a structure in which the inner and outer water layers are separated by a phospholipid bilayer membrane, which makes them unstable against various forces. It was known as a flaw at the time. According to recent research, a technology that uses various drugs dissolved in a fat emulsion with a particle size of 0.2 μm made of soybean oil and egg yolk lecithin, which has been clinically used for nutritional supplementation as a high-calorie infusion, has been developed. has achieved good results for the above purpose (Latest Medicine. 40.1806-181
3 (1980)'). This material has the characteristic that it does not have an internal water layer and can be stored extremely stably compared to liposomes. However, this substance has the property of being quickly taken up by the endothelial system of the liver and the like mentioned above. Although rapid metabolism is desirable for high-calorie infusions, it poses problems as a drug carrier for the above-mentioned purposes, such as poor drug distribution to other tissues. However, this was not necessarily desirable. Also, published patent gazette (Special Publication No. 1983-500456)
A technique is known in which a 90% fat emulsion of 100±30 nm is used as a drug carrier. This drug is also characterized by its tendency to accumulate in the reticuloendothelial system of the liver, lungs, etc., and as mentioned above, it has had problems in drug distribution to other tissues. As a means to solve the above problems, a technique has been known that uses serum riboproteins consisting of simple lipids (including sterols; the same applies herein), complex lipids, and apoliboproteins as drug carriers (especially Kaisho 60-16382
Publication No. 4). However, since this drug guides the drug to cells through the physiological and specific recognition ability of lipoproteins, it is quickly transferred to tissues via receptors, so it disappears from the blood relatively quickly. Therefore, the transfer to tissues with low receptor activity is not always sufficient, and since apolipoprotein is essential as a constituent component, it has the disadvantage of high production costs in terms of industrial technology. Furthermore, an attempt to further refine a fat emulsion with a particle size of 200 nm is known (Japanese Patent Laid-Open No. 62-029511), but this method is not stable because the small amount of egg yolk lecithin used causes the fine particles to re-agglomerate over time. He had sexual problems. Furthermore, it has a drawback in terms of stability in vivo, and is not desirable in terms of migration to other tissues.
通常、投与された薬物は、その薬物分子の持つ固有の性
質により生体内を移動分布する。そして作用部位に到達
し薬効を発現する。このとき薬効発現に必要な部位にの
み薬物が集中することが好ましいが、一般には身体全体
に薬物は分布し、不要な部位にも薬物が移動する。時に
これが副作用の原因となる。そこで、薬物の体内動態を
改善することの重要性及び必要性が生じる。
本発明者らは、上記の事情に鑑み、■薬物の薬理作用そ
のものに影響を与えることなく、■薬物の効率的な病巣
組織内への選択的移行を可能たらしめ、■しかも細網内
皮系による取り込みを低下させ、■薬物の血中濃度を持
続させ、■必要とされる薬物投与量を減じることができ
る、新しい薬物担体を検討し続けた結果、ようやく本発
明を完成させることに成功したものである。Usually, an administered drug moves and distributes within a living body due to the unique properties of the drug molecule. The drug then reaches the site of action and exerts its medicinal effect. At this time, it is preferable that the drug is concentrated only in the areas necessary for the expression of drug efficacy, but in general, the drug is distributed throughout the body, and the drug also moves to areas where it is not needed. This sometimes causes side effects. Therefore, the importance and necessity of improving the pharmacokinetics of drugs arises. In view of the above-mentioned circumstances, the present inventors have devised the following: 1) to enable efficient selective transfer of the drug into the focal tissue without affecting the pharmacological action of the drug itself; As a result of continued research into new drug carriers that can reduce the uptake of drugs, maintain the blood concentration of drugs, and reduce the required drug dosage, we have finally succeeded in completing the present invention. It is something.
本発明の要旨は、以下の諸点にある。
(1)薬物担体が、核となる脂溶性物質及びその表面を
覆う脂溶性物質の二つにより構成される脂肪乳剤であり
、リポソームのように内部に水層を持った形態でないこ
と。
(2)薬物担体中において、薬物が分散、溶解、混合ミ
セル形成、又は脂質と化学的に結合した状態で存在して
いること。
(3)粒子径が、5nm 以上2()Ona+ 未
満の範囲内にあること。
以下、これらについて詳述する。
本発明の薬物担体は、安定な脂肪乳剤としての形態を有
する。その粒子径は、5nm 以上200nn+未満
の範囲内にあることが細網内皮系による取り込み回避の
ため望ましい、この超微細化により、0.2μ擺程度の
直径を有する脂肪乳剤に比べ血中濃度が高く維持できる
・。
また特に、1100n以下がより望ましい。これは、血
管透過性の冗進した部位から血管外に容易に漏出するか
らである。
血管には種々のボアシステム(pore 5ysten
+s。
直径9na+ までの小さなボアシステムと直径25
〜70nmの大きなボアシステムとが存在するといわれ
、新生血管を含め種々の病変部位では更に透過性が増す
ことが知られている。)と呼ばれる部位や、その他の細
胞間隙が存在し、炎症、腫瘍、アテローマをはじめとす
る種々の病変部位では、血管透過性が冗進していること
が知られ、このような部位では、血管より多(の本発明
薬物担体が選択的に漏出し、病変組織内に移行する。こ
れと同時に、この薬物担体に包含されている薬物も病巣
内に移行する。このことにより、薬物が容易にそして選
、択的に病変部に移行するから、病変部位での薬物濃度
が高まりその効果を増大させることができる。また、本
発明薬物担体を適応することで、脂質と同時に薬物が投
与されるため、薬、物の徐放性及び薬物のリンパ指向性
も改善される。本発明薬物担体は、質素細胞に対する被
寅食性をも有している。
本発明の特徴は、超微粒子化した脂質を薬物担体として
用いることにある。この超微粒子化により、上述の効果
だけでなく、細網内皮系組織による取り込みを抑制する
ことなど前記の問題を一挙に解決する。これにより、薬
物の血中濃度が持続する効果をも得られる。
本発明に係る薬物担体は、従来技術である大豆油と卵黄
レシチンからなる高カロリー輸液を応用したものに比べ
、核(例えば単純脂質)に対して表層(例えば複合脂質
)をその比率において多量に使用することにより超微粒
子化を実現したことが特徴的である。
本発明の薬物担体にお・ける超微粒子化のためには、表
層(例えば複合脂質)の含量比率が15パ一セント以上
、70パーセント以下であることが望ましい。これは、
超微粒子化により、薬物担体の核の表面積が増大するた
め、表層として核を覆い安定化するために複合脂質の量
を増加させることが必要となるからである。15パ一セ
ント未満の複合脂質を用いた場合は、直径0.2μm以
上の粒子の混入が避けられず、70パーセントを越える
複合脂質を用いた場合は、リポソーム粒子の混入が避け
られない、この成分構成により、安定な超微粒子化乳剤
が得られ、このものがきわめて優れた薬物担体として利
用できることが本発明により初めて明かとなった。
即ち、本発明薬物担体は、核となる物質と表層となる物
質からなる脂肪乳剤としての形態を有すると考えられ、
■脂肪乳剤の核を構成する物質が、単純脂質、誘導脂質
、若しくは薬物そのもの自体、又はこれらの混合物であ
り、薬物担体中のその含有比率が30〜85%であり、
■脂肪乳剤の表層を構成する物質が、複合脂質、誘導脂
質、若しくは薬物そのもの自体、又はこれらの混合物で
あり、薬物担体中のその含有比率が15〜70%であり
、上記■と■との性質を同時に有することで、平均粒子
径200n+s未満の薬物を含有する薬物担体が得られ
る。
本発明において、通用した薬物が容易に薬物担体から遊
離しないように、その含有形態は、薬物担体中に分散、
溶解、薬物担体構成成分との混合ミセル形成、または薬
物担体構成成分との化学的結合であることが要求される
。
本発明の薬物担体に使用される脂質としては、天然動植
鉱物由来の単純脂質、誘導脂質及び複合脂質又はこれら
の混合物があげられる。例えば、卵黄、大豆、綿花、菜
種、トウモロコシ、胡麻、落花生、紅花、生組織、豚組
織、平組織等由来の単純脂質、誘導脂質、若しくは複合
脂質、又は、純合成的に製造された単純脂質、誘導脂質
、若しくは複合脂質のいずれでもよい。
単純脂質としては、例えば、精製大豆油、綿実油、菜種
油、胡麻油、コーン油、落花生油、サフラワー油、トリ
オレイン、トリオレイン、トリパルミチン、トリステア
リン、トリミリスチン、ドリアラキドニン等の中性脂質
を挙げることができる。また、コレステリルオレート、
コレステリルオレ−ト、コレステリルミリステート、コ
レステリルパルミテート、コレステリルアラキデート等
のステロール誘導体をも挙げることができる。
これは、血管内皮等に存在する種々のリパーゼ類により
中性脂質は比較的容易に分解されるのに対し、コレステ
ロール誘導体はこれらの酵素による分解を受けにくいた
め、体内での安定性が更に増すからである。
誘導脂質としては、例えば、コレステロールおよびステ
アリン酸、パルミチン酸、オレイン酸、リノール酸、リ
ルン酸、エイコサペンクエン酸等の脂肪酸やその誘導体
、スクワレン等が挙げられる。これらは、乳化補助剤と
しての目的でも使用される。また、アゾン等の油状化合
物も挙げられる。
複合脂質としては、例えば、卵黄、大豆、生組織、豚組
織等由来のリン脂質または、純合成的に得られるリン脂
質及び糖脂質が挙げられる。リン脂質としてホスファチ
ジルコリン、ホスファチジルエタノールアミン、ホスフ
ァチジルセリン、ホスファチジルイノシトール等が挙げ
られる。例えば、卵黄ホスファチジルコリン、大豆ホス
ファチジルコリン、ジパルミトイルホスファチジルコリ
ン、シミリストイルホスファチジルコリン、ジステアロ
イルホスファチジルコリン、ジオレオイルホスファチジ
ルコリン、ジパルミトイルホスファチジルイノシトール
等が挙げられる。それらの水素添加物も用いることがで
きる。なかでも好ましい代表例として、卵黄ホスファチ
ジルコリンを挙げることができる。糖脂質としては、セ
レプロシド等が挙げられる。ステリルグルコシド類例え
ばβ−シトステリル−β−D−グルコシド等も挙げられ
る。また、薬物担体に表面荷電を賦与するためにステア
リルアミン、ジセチルホスフェート、ホスファチジン酸
等の荷電を有する脂質をも用いることができる。
本発明を適応することができる薬物としては、医薬上許
容されるものであればよく、特に限定されることはない
。水に不溶又は難溶の薬物であっても使用することがで
きる。本発明においては、薬物は容易に担体と複合体を
形成することとなる。
水溶性の薬物においては、担体の構成成分(例えば、脂
質等)に化学的に結合させて使用することにより、本発
明薬物担体を形成させることができる。
薬物が、生体内では不安定なため、これまで投与ができ
なかった薬物であっても、本発明薬物担体を使用するこ
とにより、容易に投与することができる。本発明薬物担
体により包含された薬物は、脂質の油滴中にあり、周囲
の環境から遮断された状態で存在するので、酵素的又は
非酵素的な分解を抑制することができる。
本発明薬物担体を適応することができる薬物としては、
上述のように、特に限定を受けない。
例えば、抗炎症剤、鎮痛剤、抗アレルギー剤、抗生物質
、化学療法剤、抗癌剤、抗ウィルス剤、抗動脈硬化剤、
抗脂血症剤、抗潰瘍剤、免疫調節剤、ワクチン類、ラジ
カル除去剤、気管支拡張剤、催眠剤、トランキライザー
、局所麻酔剤、診断薬等が挙げられる。これらの例とし
て、例えば、アンシタビン、フルオロウラシル、マイト
マイシンC1マイトマイシンCフアルネシル酸アミド、
マイトマイシンCファルネシル酢酸アミド、カルモフー
ル、フトラフールバルミチン酸エステル、5−フルオロ
ウラシルミリスチン酸エステル、アドリアマイシン、ダ
ウノマイシン、アクラルビシン、マフラルビシン、ビン
ブラスチン、ビンクリスチン、シタラビン脂肪酸エステ
ル、ミドクン、エストラムスチンなどの抗癌剤や、ジク
ロロフラバン等の抗ウィルス剤、ステロイド剤(例えば
デキサメタシンパルミチン酸エステル、ハイドロコーチ
シンパルミチン酸エステル、プレドニゾロンパルミチン
酸エステル、デキサメタシンステアリン酸エステル、メ
チルプレドニゾロン、バラメタシン、フルオシノロンア
セトニド、ベクタメタシンプロピオン酸エステル、ハイ
ドロコーチシン脂肪酸エステル、アルドステロン、スピ
ロノラクトンなど)、及び非ステロイド剤(例えばイブ
プロフェン、フルフェナム酸、ケトプロフェン、ツェナ
セチン、アンチピリン、アミノピリン、フェニルブタシ
ンインドール酢酸エステル、ビフェニリルプロピオン酸
誘導体、インドメタシン、インドメサシンエトキシカル
ボニルメチルエステル、インドメタシンステアリルエス
テル、金チオリンゴ酸セチルエステル、ジクロフェナク
、アセチルサリチル酸及びその誘導体など)が挙げられ
る。トラニラスト、テトラフェン、アゼラスチン等の抗
アレルギー剤も用いることができる。抗生物質及び化学
療法剤としては、例えば、テトラサイクリン類、エリス
ロマイシン、ミデカマイシン、アムホテリシン、ナリジ
クス酸、グリセオフルビン、ミノサイク、リンなどが挙
げられる。プロスタグランデイン剤の例として、PGE
I 、PGAI 、PCAIアルキルエステル、PGE
Iアルキルエステル、PGE1誘導体、PG12誘導体
、PGD2誘導体などを用いることができる。ジフェン
ヒドラミン、オルフェナジリン、クロルフェノキサミン
、クロルフェニラミン、プロメタシン、メタリジン、シ
プロヘブタジン、ロキサチジンアセテートなどの抗ヒス
タミン剤も挙げられる。また、リドカイン、ベンツ゛カ
イン、ダントロレン、コカイン、テトラカイン、ピロカ
ルン、メピラカイン等およびこれらの誘導体等の局所麻
酔剤も挙げられる。肝障害改善剤(例えば、マロチラー
ト、グリチルレチン酸、アセチルグリチルレチン酸エチ
ルエステル、グリチルレチン酸メチルエステルなど)や
抗潰瘍剤(例えば、ファルネソール、ゲラニオール、ゲ
ファルネート、テプレノン、プラウノトール、ソファル
コン等)が挙げられる。中枢神経作用薬(例えば、フェ
ノバルビクール、メタクアロン、ヘロイン、ジアゼパム
、メダゼパム、フラゼパム、クロチアゼパム、二チプラ
ム、メタリジン、ブタリジン、アジフェニン、メタンフ
ェタミン、イミプラミン、クロルイミプラミン、アミト
リブチリン、ミアンセリン、トリメタジオン、フェンス
キシミド、テトラベンザミド、ベンズキナミド、カンフ
ル、ジモルホラミン、ストリキニーネ、クロルプロマジ
ン、プロメタシン、プロクロルペラジン、メキタジン、
トリフルプロマシン、レポメブロマジン、ジフェニドー
ル等およびこれらの誘導体)が挙げられる。脳血管拡張
剤(例えば、シンナリジン等)も挙げることができる。
気管支拡張剤として、ベストフィリンやその他のテオフ
ィリン誘導体、メチルエフェドリン等を挙げることがで
きる。抗コリン剤(例えば、ベンズトロピン、フィゾス
チグミン、アトロピン、スコポラ文ン等)、副交感神経
遮断剤(例えば、オキシフェンシクリミン、ピレンゼピ
ン、エトミドリン等)、カルシウムブロッカ−(例えば
、ジルチアゼム、ニフェジピン、ベラパミル等)、α−
プロフカ−(例えば、ジベンザミン、フェノキシベンザ
ミン等)、鎮咳剤(例えば、ノスカピン、デキストロメ
トルファン、ベストフィリン、ペンプロペリンなど)、
前立腺肥大治療剤(例えば、ガストロン、オキセンゾロ
ン等)、緑内障治療薬(例えば、ピロカルビン等)、平
滑筋作用薬(例えば、スパルテイン、ババベリン等)、
抗脂血症治療薬(例えば、クロフィブレート、シムフィ
プレート、プロブコール等)なども挙げられる。その他
、例えば、アミノ酸、ビタミン類、ジラゼップ、ユビデ
カレノン、フラボキセート、サイクロスポリン、インフ
ルエンザ等のワクチン、ジベンズチオン、ジフェニルビ
ラリン、フェノバリニューム、メタジオン、トフィソパ
ム、リモネンなど)も挙げられる。
抗酸化剤、(例えば、トコフェロール、フラボン誘導体
、没食子酸誘導体、コーヒー酸誘導体、ゴシポール、セ
ザモール、オキシ脂肪酸類、カンフエン、シネオール、
ロスマノール、オイゲノール、フィロズルシン類、カテ
キン類、リグナン類縁体、p−クマリン酸、ステロール
類、テルペン類、ブロモフェノールなど)も本薬物担体
の構成要素の一つとして本発明薬物担体を形成させるこ
とができる。
また、グアイアズレンや精油性生薬(例えば、キョウニ
ン油、ウィキョウ油、タイム油、テレピン油、ユーカリ
油、パーム油、ケシ油、ツバキ油ハツカ油、チョウジ油
、ミント油、セージ油、その他の香辛用生薬成分など)
等も、本薬物担体の構成要素の一つとして本発明薬物担
体を形成させることができる。
診断薬としては、例えば、放射性同位元素で標識された
化合物、放射性医薬品やヨウ素系X線造影剤であるヨー
ド化ケシ油脂肪酸エステルなどが挙げられる。
本発明薬物担体を適応することができる薬物としては、
上述のごとく、特に限定を受けないが、薬物担体として
持つ性質の特徴から判断するとき、炎症、l1ffi瘍
、血管、或いは免疫・リンパ系に関与する薬物が一般に
望ましい。
本発明薬物担体における薬物濃度は、この薬物の生物学
的活性に従って、薬物担体中台量比率が85%を越えな
い範囲で適宜増減することができる。
また、本発明薬物担体を用いた製剤中の本発明薬物担体
の濃度は所望に応じ適宜増減することができ任意である
。
本発明薬物担体及びこれを使用した製剤の製造にあたっ
ては、従来から行われてきた種々の乳剤製造法を応用す
ることができる。例えば、薬物を含めた全構成成分をマ
ントン−ガラリン型ホモジナイザー、ミクロフルイダイ
ザー、超音波ホモジナイザー等により充分に微細化して
形成せしめる方法や、界面活性剤(例えば胆汁酸)、水
溶性溶媒(例えばエタノール、ポリエチレングリコール
)等で可溶化した後に透析やゲル濾過により界面活性剤
や水溶性溶媒等を除去して形成せしめる方法等で製造す
ることができる。この時、乳化補助剤として脂肪酸ある
いはその誘導体等を加えることもできる。また、予め上
述の方法で作製した直径200nm以上の粒子を含まな
い脂肪乳剤に薬物を添加して得ることもできる。
本発明薬物担体の形状や粒子径は、電子顕微鏡、光散乱
方式の粒子径分析装置、メンブレンフィルターによる濾
過等により容易に確認することができる。 本発明薬物
担体の製剤の任意の成分゛として、一般注射剤に用いら
れる添加剤及び補助物質などを挙げることができる。例
えば、酸化防止剤、防腐剤、安定化剤、等張化剤、緩衝
剤等を挙げることができる。これらの添加剤、補助物質
等の要求量及び最適量は、その目的に応じて変化させる
ことができる。
上記のようにして得られる本発明薬物担体は、必要に応
じて滅菌(例えば濾過滅菌や高圧蒸気滅菌)し、窒素ガ
スとともにアンプル中に封入することができる。又、必
要に応じて凍結乾燥することができる。凍結乾燥させた
本発明薬物担体は、適当な溶液の添加によって復元する
ことができる。
本発明薬物担体は、人又は動物の静脈内に投与するのが
一般的であるが、必要に応じて動脈内、筋肉内、及び皮
下等に投与することもできる。
また、本発明薬物担体は、点眼剤、点鼻剤、経口投与剤
、または坐剤等としても使用することができる。この場
合においては、医薬上許容される基剤、賦形剤等の添加
剤を任意の成分として挙げることができる。The gist of the present invention lies in the following points. (1) The drug carrier is a fat emulsion consisting of a core fat-soluble substance and a fat-soluble substance covering its surface, and does not have an internal aqueous layer like liposomes. (2) In the drug carrier, the drug exists in a state of being dispersed, dissolved, forming mixed micelles, or chemically bonded to lipids. (3) The particle diameter is within the range of 5 nm or more and less than 2()Ona+. These will be explained in detail below. The drug carrier of the present invention is in the form of a stable fat emulsion. It is desirable that the particle size be within the range of 5 nm or more and less than 200 nm+ to avoid uptake by the reticuloendothelial system.This ultra-fine refinement results in a lower blood concentration than a fat emulsion with a diameter of about 0.2 μm. Can be maintained high. In particular, it is more desirable that the thickness be 1100n or less. This is because it easily leaks out of blood vessels from areas with increased vascular permeability. Blood vessels have various bore systems (pore 5ysten).
+s. Small bore systems up to diameter 9na+ and diameter 25
It is said that a large pore system of ~70 nm exists, and it is known that the permeability increases further at various lesion sites including new blood vessels. ) and other intercellular spaces, and it is known that vascular permeability is increased at various lesion sites such as inflammation, tumors, and atheroma. A larger amount of the drug carrier of the present invention selectively leaks out and migrates into the diseased tissue.At the same time, the drug contained in this drug carrier also migrates into the lesion. Since the drug is selectively transferred to the lesion site, the concentration of the drug at the lesion site increases and its effect can be increased.Also, by applying the drug carrier of the present invention, the drug can be administered simultaneously with lipids. Therefore, the sustained release properties of drugs and substances and the lymphotropism of drugs are also improved.The drug carrier of the present invention also has phagocytosis for simple cells.The feature of the present invention is that ultrafine lipid particles This ultrafine particle formation not only provides the above-mentioned effects, but also solves the aforementioned problems at once by suppressing uptake by the reticuloendothelial tissue.This allows the drug to be absorbed into the bloodstream. The drug carrier according to the present invention has a higher concentration than the core (for example, simple lipids) and the surface layer ( The drug carrier of the present invention is characterized in that ultrafine particles are achieved by using a large amount of the drug carrier (for example, complex lipids) at that ratio. It is desirable that the content ratio of is 15% or more and 70% or less.
This is because ultrafine particle formation increases the surface area of the core of the drug carrier, and therefore it is necessary to increase the amount of complex lipid in order to cover and stabilize the core as a surface layer. If less than 15% of the composite lipid is used, contamination of particles with a diameter of 0.2 μm or more is unavoidable, and if more than 70% of the composite lipid is used, the contamination of liposome particles is unavoidable. The present invention revealed for the first time that a stable ultrafine emulsion can be obtained depending on the component composition, and that this emulsion can be used as an extremely excellent drug carrier. That is, the drug carrier of the present invention is considered to have the form of a fat emulsion consisting of a core substance and a surface substance,
- The substance constituting the core of the fat emulsion is a simple lipid, a derived lipid, the drug itself, or a mixture thereof, and the content ratio in the drug carrier is 30 to 85%;
■The substance constituting the surface layer of the fat emulsion is a complex lipid, a derived lipid, the drug itself, or a mixture thereof, and the content ratio of the substance in the drug carrier is 15 to 70%. By having these properties at the same time, a drug carrier containing a drug with an average particle size of less than 200n+s can be obtained. In the present invention, in order to prevent the commonly used drug from being easily released from the drug carrier, the containing form is dispersed in the drug carrier,
Dissolution, mixed micelle formation with drug carrier components, or chemical bonding with drug carrier components is required. The lipids used in the drug carrier of the present invention include simple lipids derived from natural animal and plant minerals, derived lipids, complex lipids, or mixtures thereof. For example, simple lipids, derived lipids, or complex lipids derived from egg yolk, soybean, cotton, rapeseed, corn, sesame, peanut, safflower, raw tissue, pig tissue, flat tissue, etc., or simple lipids produced purely synthetically. , derived lipids, or complex lipids. Examples of simple lipids include neutral lipids such as refined soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, triolein, tripalmitin, tristearin, trimyristin, and doliarachidonin. can be mentioned. Also, cholesteryl oleate,
Mention may also be made of sterol derivatives such as cholesteryl oleate, cholesteryl myristate, cholesteryl palmitate and cholesteryl arachidate. This is because while neutral lipids are relatively easily degraded by various lipases present in vascular endothelium, cholesterol derivatives are less susceptible to degradation by these enzymes, which further increases their stability in the body. It is from. Examples of the derived lipids include cholesterol and fatty acids such as stearic acid, palmitic acid, oleic acid, linoleic acid, lylunic acid, and eicosapencitric acid, derivatives thereof, squalene, and the like. They are also used for purposes as emulsification aids. Also included are oily compounds such as azone. Examples of complex lipids include phospholipids derived from egg yolk, soybean, raw tissue, pig tissue, etc., and phospholipids and glycolipids obtained by pure synthesis. Examples of phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and the like. Examples include egg yolk phosphatidylcholine, soybean phosphatidylcholine, dipalmitoylphosphatidylcholine, simyristoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylinositol, and the like. Hydrogenated versions thereof can also be used. Among them, egg yolk phosphatidylcholine is a preferred representative example. Examples of glycolipids include cereproside. Also included are steryl glucosides such as β-sitosteryl-β-D-glucoside. Furthermore, charged lipids such as stearylamine, dicetyl phosphate, and phosphatidic acid can also be used to impart a surface charge to the drug carrier. The drug to which the present invention can be applied is not particularly limited as long as it is pharmaceutically acceptable. Even drugs that are insoluble or poorly soluble in water can be used. In the present invention, the drug easily forms a complex with the carrier. In the case of water-soluble drugs, the drug carrier of the present invention can be formed by chemically bonding them to constituent components of the carrier (eg, lipids, etc.). Even if the drug is unstable in vivo and could not be administered up to now, it can be easily administered by using the drug carrier of the present invention. Since the drug encapsulated by the drug carrier of the present invention is present in lipid oil droplets and is isolated from the surrounding environment, enzymatic or non-enzymatic decomposition can be suppressed. Drugs to which the drug carrier of the present invention can be applied include:
As mentioned above, there are no particular limitations. For example, anti-inflammatory agents, analgesics, anti-allergic agents, antibiotics, chemotherapy agents, anti-cancer agents, anti-viral agents, anti-arteriosclerotic agents,
Examples include antilipemic agents, antiulcer agents, immunomodulators, vaccines, radical scavengers, bronchodilators, hypnotics, tranquilizers, local anesthetics, diagnostic agents, and the like. Examples of these include, for example, ancitabine, fluorouracil, mitomycin C1 mitomycin C farnesylic acid amide,
Anticancer drugs such as mitomycin C farnesyl acetate amide, carmofur, futrafur balmitate, 5-fluorouracil myristate, adriamycin, daunomycin, aclarubicin, mafrarubicin, vinblastine, vincristine, cytarabine fatty acid ester, midocun, estramustine, and dichloroflavan. antiviral agents such as dexamethacin palmitate, hydrocorchicin palmitate, prednisolone palmitate, dexamethacin stearate, methylprednisolone, valamethacin, fluocinolone acetonide, vectormethacin propionic acid ester, hydrocortiscin fatty acid ester, aldosterone, spironolactone, etc.), and non-steroidal agents (e.g. ibuprofen, flufenamic acid, ketoprofen, zenacetin, antipyrine, aminopyrine, phenylbutacin indole acetate, biphenylylpropionic acid derivatives, indomethacin, Indomethacin ethoxycarbonyl methyl ester, indomethacin stearyl ester, gold thiomalic acid cetyl ester, diclofenac, acetylsalicylic acid and derivatives thereof, etc.). Antiallergic agents such as tranilast, tetrafen, azelastine, etc. can also be used. Examples of antibiotics and chemotherapeutic agents include tetracyclines, erythromycin, midecamycin, amphotericin, nalidixic acid, griseofulvin, minocyc, phosphorus, and the like. As an example of a prostaglandin agent, PGE
I, PGAI, PCAI alkyl ester, PGE
I alkyl esters, PGE1 derivatives, PG12 derivatives, PGD2 derivatives, etc. can be used. Also included are antihistamines such as diphenhydramine, orphenaziline, chlorfenoxamine, chlorpheniramine, promethacin, metarizine, cyprohebutadine, and roxatidine acetate. Also included are local anesthetics such as lidocaine, benzocaine, dantrolene, cocaine, tetracaine, pilocarne, mepiracaine, and derivatives thereof. Examples include liver disorder improving agents (eg, malotylate, glycyrrhetinic acid, acetyl glycyrrhetinic acid ethyl ester, glycyrrhetinic acid methyl ester, etc.) and anti-ulcer agents (eg, farnesol, geraniol, gefarnate, teprenone, plaunotol, sofalcon, etc.). Central nervous system agents (e.g., phenobarbicur, methaqualone, heroin, diazepam, medazepam, frazepam, clotiazepam, nitipram, methalyzine, butaridine, adifenine, methamphetamine, imipramine, chlorimipramine, amitributyline, mianserin, trimethadione, fenximide, tetra Benzamide, benzquinamide, camphor, dimorpholamine, strychnine, chlorpromazine, promethacin, prochlorperazine, mequitazine,
triflupromacine, lepomebromazine, diphenidol, etc. and derivatives thereof). Cerebral vasodilators (eg, cinnarizine, etc.) may also be mentioned. Examples of bronchodilators include bestfilline, other theophylline derivatives, methylephedrine, and the like. Anticholinergic agents (e.g., benztropine, physostigmine, atropine, scopolymone, etc.), parasympatholytic agents (e.g., oxyphencyclimine, pirenzepine, etomidrine, etc.), calcium blockers (e.g., diltiazem, nifedipine, verapamil, etc.) , α−
Profka (e.g., dibenzamine, phenoxybenzamine, etc.), antitussives (e.g., noscapine, dextromethorphan, bestfilin, penproperine, etc.),
Prostatic hyperplasia therapeutics (e.g., gastron, oxenzolone, etc.), glaucoma therapeutics (e.g., pilocarbin, etc.), smooth muscle agonists (e.g., spartein, bababerine, etc.),
Also included are antilipidemic drugs (eg, clofibrate, simfiplate, probucol, etc.). Other examples include amino acids, vitamins, dirazep, ubidecarenone, flavoxate, cyclosporine, vaccines such as influenza, dibenzthione, diphenylbilarin, phenobalinum, metadione, tofisopam, limonene, etc.). Antioxidants, (e.g. tocopherols, flavone derivatives, gallic acid derivatives, caffeic acid derivatives, gossypol, cezamol, oxyfatty acids, camphene, cineole,
Rosmanol, eugenol, phyllodulcins, catechins, lignan analogs, p-coumaric acid, sterols, terpenes, bromophenol, etc.) can also be used as one of the components of the drug carrier to form the drug carrier of the present invention. . In addition, guaiazulene and essential oil-based herbal medicines (for example, kyonin oil, fennel oil, thyme oil, turpentine oil, eucalyptus oil, palm oil, poppy oil, camellia oil, clove oil, mint oil, sage oil, and other spice herbal medicines) ingredients, etc.)
The drug carrier of the present invention can also be formed as one of the constituent elements of the drug carrier of the present invention. Examples of diagnostic agents include compounds labeled with radioactive isotopes, radiopharmaceuticals, and iodinated poppy oil fatty acid esters that are iodine-based X-ray contrast agents. Drugs to which the drug carrier of the present invention can be applied include:
As mentioned above, although there is no particular limitation, drugs that are involved in inflammation, l1ffi tumors, blood vessels, or the immune/lymphatic system are generally desirable when judged from their characteristics as drug carriers. The concentration of the drug in the drug carrier of the present invention can be appropriately increased or decreased depending on the biological activity of the drug, as long as the ratio of the amount in the drug carrier does not exceed 85%. Further, the concentration of the drug carrier of the present invention in a preparation using the drug carrier of the present invention can be increased or decreased as desired. In the production of the drug carrier of the present invention and formulations using the same, various conventional emulsion production methods can be applied. For example, there are methods in which all constituents including drugs are sufficiently micronized using a Manton-Gallin type homogenizer, microfluidizer, ultrasonic homogenizer, etc., surfactants (e.g. bile acids), water-soluble solvents (e.g. ethanol), etc. , polyethylene glycol), etc., and then removing surfactants, water-soluble solvents, etc. by dialysis or gel filtration. At this time, fatty acids or derivatives thereof can also be added as emulsification aids. Alternatively, the drug can also be obtained by adding the drug to a fat emulsion that does not contain particles with a diameter of 200 nm or more and is prepared in advance by the method described above. The shape and particle size of the drug carrier of the present invention can be easily confirmed using an electron microscope, a light scattering particle size analyzer, filtration using a membrane filter, or the like. Optional components of the drug carrier formulation of the present invention include additives and auxiliary substances used in general injections. For example, antioxidants, preservatives, stabilizers, tonicity agents, buffers, etc. can be mentioned. The required amount and optimum amount of these additives, auxiliary substances, etc. can be changed depending on the purpose. The drug carrier of the present invention obtained as described above can be sterilized (for example, filter sterilization or high-pressure steam sterilization) if necessary, and sealed in an ampoule together with nitrogen gas. Moreover, it can be freeze-dried if necessary. The lyophilized drug carrier of the present invention can be reconstituted by adding an appropriate solution. The drug carrier of the present invention is generally administered intravenously to humans or animals, but it can also be administered intraarterially, intramuscularly, subcutaneously, etc., if necessary. The drug carrier of the present invention can also be used as eye drops, nasal drops, oral preparations, suppositories, and the like. In this case, additives such as pharmaceutically acceptable bases and excipients can be mentioned as optional components.
本発明によれば、薬物の利用価値を著しく高めることが
できる。本発明薬物担体の効果は、従来の問題点′を克
服し、■病巣への薬物移行性を改善したこと、■細網内
皮系による取り込みを抑制したこと、■包含する薬物の
血中濃度の持続を可能としたこと、■保存時の安定性を
確保したこと、■製造コストを低減させたこと、等に集
約することができる。これらの効果は、本発明により初
めて成されたものである。
本発明薬物担体の構成成分は、従来から医療現場におい
て医療用として用いられてきた医i−h許容される脂質
を主とするため、極めて安全に使用することができるこ
とも特徴である。According to the present invention, the utility value of drugs can be significantly increased. The effects of the drug carrier of the present invention are that it overcomes the conventional problems, ① improves drug migration to lesions, ② inhibits uptake by the reticuloendothelial system, and ② lowers the blood concentration of the drug it contains. This can be summarized as: making it sustainable; ■ ensuring stability during storage; and ■ reducing manufacturing costs. These effects have been achieved for the first time by the present invention. Since the constituent components of the drug carrier of the present invention are mainly medically acceptable lipids that have been conventionally used for medical purposes in medical settings, it is also characterized in that it can be used extremely safely.
以下に本発明薬物担体の製造に関する実施例を揚げて本
発明を更に詳しく説明するが、本発明がこれらのみに限
定されるものではないことは明白である。
実施例1
トリオレイン27mgに卵黄レシチン38mg及びグア
イアズレン(抗炎症剤) 10o+gを加え、これに
生理食塩水10m1を加えてプローブ型超音波ホモジナ
イザー(プランソン ソニファイアー モデル 185
)を用いて、水冷下、60分間超音波処理を施す、生成
するグアイアズレンを含有した薬物担体は、青色で澄明
である。このものの光散乱粒子径測定装置による平均粒
子径は、26.4n−であった。また、電子顕微鏡によ
る形態観察では、均一な球形の超微粒子として認められ
た。リポソームのような脂質二分子膜は認められなかっ
た。
また、0.2μ−の濾過メンブレンを100%通過し、
0.2μm以上の粒子を含まないことが判った。
実施例2
卵黄レシチン2.5mg、及びグアイアズレン10mg
を加え、これに生理食塩水10m1を加えてプローブ型
超音波ホモジナイザー(プランソン ソ偽ファイア−モ
デル 185)を用いて、水冷下に60分間超音波処理
を施す、生成するグアイアズレンを含有した薬物担体の
光散乱粒子径測定装置による平均粒子径は、48.4n
m であった、また、0.2μ園の濾過メンブレンを
100%通過し、0.2μ−以上の粒子を含まないこと
が判った。
実施例3
トリオレイン10hg に卵黄レシチン100+sg
及びデキサメタシン(抗炎症剤)に脂肪酸を化学的に結
合させた化合物(デキサメタシンパルミチン酸エステル
) 4mgを加え、これに0.24yI のグリセリ
ン水溶液10+mlを加えてプローブ型超音波ホモジナ
イザー(プランソン ソニファイアーモデル 185)
を用いて、水冷下、60分間超音波処理を施す、生成す
るデキサメタシンパルミチン酸エステルを含有した薬物
担体は、僅かに青白色で澄明である。このものの光散乱
粒子径測定装置による平均粒子径は、29.9n+s
であった。
また、0.2μmの濾過メンブレンを100%通過し、
0.2μm以上の粒子を含まないことが判った。
実施例4
トリオレイン80mgに、コレステリルリル−ト20m
g 、卵黄レシチン100+ag 及びデキサメタシ
ンパルミチン酸エステル4n+g を加えた後、これ
に0.21 のグリセリン水溶液10−1を加えてプ
ローブ型超音波ホモジナイザー(プランソンソニファイ
アー モデル 185)を用いて、水冷下、60分間超
音波処理を施す、生成するデキサメタシンパルミチン酸
エステルを含有した薬物担体は、僅かに青白色で澄明で
ある。このものの光散乱粒子径測定装置による平均粒子
径は、30.6nm であった。また、0.2μmの
濾過メンブレンを100%通過し、0.2μm以上の粒
子を含まないことが判った。
実施例5
コレステリルリル−ト10100l1卵黄レシチン10
0+ag 及びデキサメタシンパルミチン酸エステル
4mg を加え、これに0.24fl のグリセリ
ン水溶液10m1を加えてプローブ型超音波ホモジナイ
ザー(プランソン ソニファイア−モデル 185)を
用いて、60℃に加温しながら60分間超音波処理を施
す、生成するデキサメタシンパルミチン酸エステルを含
有した薬物担体は、僅かに青白色で澄明である。このも
のの光散乱粒子径測定装置による平均粒子径は、22.
7nm であった。
マタ、0.2μmの濾過メンブレンを100%ill遇
シ、0.2μm以上の粒子を含まないことが判った。
実施例6
トリオレイン100mg に卵黄レシチン100a+
g。
及びジフェンヒドラミン(抗ヒスタミン剤) 10a+
gを加え、これに0.24M のグリセリン水溶液1
0a+1を加えてプローブ型超音波ホモジナイザー(プ
ランソン ソニファイアー モデル 185)を用いて
、水冷下、60分間超音波処理を施す、生成するジフェ
ンヒドラミンを含有した薬物担体は、僅かに青白色で澄
明である。このものの光散乱粒子径測定装置による平均
粒子径は、31 、6n■ であった。また、0.2μ
mの濾過メンブレンを100%通過し、0.2μm以上
の粒子を含まないことが判った。
実施例7
トリオレイン100mg に卵黄レシチン100mg
を加え、これに0.24?t のグリセリン水溶液1
0+nlを加えてプローブ型超音波ホモジナイザー(プ
ランソン ソニファイアー モデル 185)を用いて
、水冷下、60分間超音波処理を施す。生成する薬物担
体は、僅かに青白色で澄明である。このものの光散乱粒
子径測定装置による平均粒子径は、47.2nm で
あった。また、0.2μ課の濾過メンブレンを100%
通過し、0.2μm以上の粒子を含まないことが判った
。
ビンブラスチン(抗癌剤)に脂肪酸を化学的に結合させ
た化合物(ビンブラスチンバルミチン酸エステル)50
0μgを、上で得られた薬物担体に加え、穏やかに6時
間混合、攪拌して薬物担体内に薬物を取り込ませた。こ
のようにして、薬物を含有した薬物担体を得た。
5−フルオロウラシル(抗癌剤)に脂肪酸を化学的に結
合させた化合物(5−フルオロウラシルパルミチン酸エ
ステル)500μgを、上で得られた薬物担体に加え、
穏やかに6時間混合、攪拌して薬物担体内に薬物を取り
込ませた。このようにして、薬物を含有した薬物担体を
得た。
シタラビン(抗癌剤)に脂肪酸を化学的に結合させた化
合物(シタラビンレブリン酸エステル)500μgを、
上で得られた薬物担体に加え、穏やかに6時間混合、攪
拌して薬物担体内に薬物を取り込ませた。このようにし
て、薬物を含有した薬物担体を得た。
実施例8
トリオレイン80mgに、コレステリルリル−) 20
+++g 、及び卵黄レシチン100mg に0.2
4Mのグリセリン水溶液10m1を加えてプローブ型超
音波ホモジナイザー(プランソン ソニファイアー モ
デル 185)を用いて、水冷下、60分間超音波処理
を施す。生成する薬物担体は、僅かに青白色で澄明であ
る。このものの光散乱粒子径測定装置による平均粒子径
は、19.1nmであった。第1図にはその分析結果を
示した。また0、2μmの濾過メンブレンを100%通
過し、0.2μm以上の粒子を含まないことが判った。
実施例9
精製大豆油20ttrgに卵黄レシチン20mgを゛加
え、これに0.24M のグリセリン水溶液10m1
を加えてプローブ型超音波ホモジナイザー(プランソン
ソニファイアー モデル 185)を用いて、水冷下、
60分間超音波処理を施す。生成する薬物担体は、僅か
に青白色で澄明である。このものの光散乱粒子径測定装
置による平均粒子径は、16.1nmであった。また、
0.2μmの濾過メンブレンを100%通過し、0.2
μm以上の粒子を含まないことが判った。
また、上記と同様に精製大豆油40mgを使用して薬物
担体を製造した。生成する薬物担体は、僅かに青白色で
澄明である。このものの光散乱粒子径測定装置による平
均粒子径は、37.7n+aであった。
また、0.2μmの濾過メンブレンを100%通過し、
0.2μm以上の粒子を含まないことが判つた。
実施例1O
大豆油10gに卵黄レシチン10gを加え、これに0.
24Mのグリセリン水溶液1℃を加えてミクロフルイダ
イザーを用いて乳化する。生成する薬物担体は、0.2
μlの濾過メンブレンを100%通過し、0.2μm以
上の粒子を含まないことが判った。
[本発明薬物担体の安定性試験]
試験例1−1
実施例1で得た試料を窒素ガスとともに容量1、mlの
褐色のアンプルに封入し、常法に従い60℃で4週間の
虐待試験を行った。グアイアズレンの残存率は98.3
% 以上であり、本発明薬物担体は薬物安定性に効果を
有することが確認された。
試験例1−2
上記実施例1、実施例3及び実施例4で得た試料を窒素
ガスとともに容量1mlの褐色のアンプルに封入した。
これをオートクレーブにより高圧蒸気滅菌処理した後、
試料の粒子径を光散乱粒子径測定装置で測定したところ
、それぞれ処理前と有意な差はなく、凝集や粒子径の増
大は認められなかった。また、このものを4℃で6力月
保存しておいたところ、凝集等の変化を認めなかった。
試験例1−3
上記実施例3で得た試料を常法に従い凍結乾燥した。そ
の後、注射用蒸留水を加えて攪拌、復元したのち、試料
の粒子径を光散乱粒子径測定装置で測定したところ、平
均粒子径28.3nmであり、有意な凝集や粒子径の増
大は認められず均一に分散していた。
[本発明の有用性試験]
試験例2−1
実施例3と同様に作製した 3H標識デキサメタシンパ
ルミチン酸エステルを含有する本発明薬物坦体を検体試
料とした。対照試料として、従来技術である直径0.2
μmの脂肪乳剤を用いた。この対照試料は ’HIKf
iデキサメタシンパルミチン酸エステル4 tag s
精製大豆油100n+g、卵黄レシチン12mgに0.
24Mグリセリン水溶液10n+1を加えて乳化したも
のである。
検体試料及び対照試料をラットに静脈内投与した後の血
中濃度推移を検討した。
第2図に検体試料及び対照試料をデキサメタシン換算で
0.05+ag/kgの投与量でSD系雄性ラット(体
重的210g )の尾静脈に静脈内投与したときの血漿
中捻放射能の推移をデキサメタシン換算で示した。対照
試料は速やかに血漿中より消失したが、検体試料の血漿
からの消失は緩やかであり、分布相における消失半減期
は、それぞれ10.5分、及び5.5分である。
試験例2−2
実施例4と同様に作製した 3H標識デキサメタシンパ
ルミチン酸エステルを含有する本発明゛薬物担体を検体
試料と、試験例2−1で用いたと同じ対照試料を用いて
、カラゲニン浮腫による炎症部位への薬物移行を検体試
料と対照試料とを比較した。
SD系雄性ラット(体重的195g )の片側足随に0
.5%λ−カラゲニン0.1ml を皮下投与し、カ
ラゲニン浮腫を作成した。カラゲニン投与2時間後、尾
静脈内にデキサメタシン換算で 0.5mg/kgの用
量で検体試料と対照試料を静脈内投与した。静脈内投与
後、60分で腹部大動脈から採血し血漿を得るとともに
、炎症足及び反対足(対照足)を足首関節より切断した
。各々の放射能は、試料燃焼装置で処理した後に測定し
た。
第1表において、検体試料は対照試料に比べて、多量の
薬物が炎症部位(浮腫部分)に移行し、炎症部位への強
い集積性が認められた。炎症により生じた浮腫部分には
、対照試料の5.7倍の薬物濃度が認められた。
試験例2−3
第2表は、上記の試験例2−2で用いたと同じ検体試料
と対照試料を用い、ラフト胸膜炎モデルにおける胸膜中
への薬物移行と主要組織への移行を比較検討したもので
ある。
SD系雄性ラット(体重的300g )の胸腔内に2%
λ−カラゲニンO,1ml を注入した。カラゲニ
ン投与2.5時間後、尾静脈内にデキサメタシン換算で
1.25+mg/kgの投与量で検体試料及び対照試
料を静脈内投与した。静脈内投与後30分で腹部大動脈
より脱血した後、胸膜を生理食塩液で洗いだして10m
1とし放射能を測定した。同時に主要臓器も摘出し、各
々の放射能は、試料燃焼装置で処理した後に測定した。
第2表 炎症部位及び主要組織への移行表示はデキサメ
タシン換算での平均値
第2表において、検体試料は対照試料に比べて多量の薬
物が炎症部位(胸膜)に移行し炎症部位への強い集積性
が認められた。膨水中には対照試料の3.9倍の薬物が
認められた。主要臓器への分布において、肝臓及び膵臓
というm精内皮系の発達した組織への移行は、検体試料
がきわめて低い値を示した。
試験例2−4
上記の試験例2−2で用いたと同じ検体試料と対照試料
を、BALB/C系雄性マウス(体重約25g)に静脈
内投与し、30分後の血漿中及び肝臓中の米麦化体濃度
と代謝物であるデキサメタシン濃度を測定した。投与量
は、デキサメタシン換算で5mg/kgとした。
第3表には薄層クロマトグラフィーにより未変化体(デ
キサメタシンバルミチン酸エステル、濃度はデキサメタ
シン換算で表示)と代謝物(デキサメタシン)を分離定
量した後の各々の濃度を示した。
検体試料の場合、血漿中濃度は高く、肝臓への分布は低
かった。また、血簗中では大半が未変化体として存在し
た。本発明薬物担体を用いた場合、薬物の血中濃度維持
と細網内皮系への取り込みの抑制効果が明白である。
表示は(平均士標準偏差)
(以下次頁)
試験例2−5
試験例2−2で用いたと同じ検体試料と対照試料、及び
リン酸デキサメタシン生理食塩水溶液について、カラゲ
ニン浮腫抑制を指標として薬理効果を検討した。
SD系雄性ラット(体重約160g >の片側定限に、
λ−カラゲニン(0,5χ、 0.1+ml )を皮下
投与し、30分後に検体試料、対照試料及びリン酸デキ
サメタシンを尾静脈より静脈内投与した。コントロール
群には生理食塩水を投与した。カラゲニン投与前及び投
与5時間後に定容積を常法にて測定し、浮腫抑制率を求
めた。
第3図にその用量作用曲線(デキサメタシン換算で表示
)を示した。50%浮腫抑制用量(EDs。
)を第4表に示した。
検体試料は、従来技術である対照試料では改善されなか
ったこの種の炎症においても、他の二つの試料に比べて
約二倍の抗炎症活性を有することが明白である。すなわ
ち、本発明薬物担体の効果が薬物効果の増強作用として
確認された。これは本発明薬物担体を用いることで薬物
が効率的に病巣へ移行した結果によることが明確である
。
後肉芽腫、胸腺及び副腎を摘出し重量を測定した。
第5表より、検体試料は対照試料及びリン酸デキサメタ
シンに比べて、明らかに肉芽腫形成抑制作用が強(、ま
た胸腺や副腎の萎縮作用が少ないことがわかる。すなわ
ち、検体試料は薬理効果が強く副作用が少ないことが示
された。
試験例2−6
試験例2−2で用いたと同じ検体試料と対照試料、及び
リン酸デキサメタシン生理食塩水溶液について、カラゲ
ニン肉芽腫抑制を指標として薬理効果を、また、tfi
lilと副腎重量を検討した。
SD系雄性ラット(体重約160g )の背部皮下に、
λ−カラゲニン(2,0χ、 4.0a+1)を皮下投
与し、5日後より3日間、各々の試料を1日1回、計3
回尾静脈より静脈内投与した。薬物投与量は、デキサメ
タシン換算で1回当り0.05mg/kgとした。
コントロール群には生理食塩水を投与した。8日表示は
(平均値上標準偏差)
試験例2−7
腫瘍部位への移行性を確認する試験を行った。
P388白血病細胞をCDFl系雄性マウス(体重約2
5g)の右前足踵部皮下に、108個移植した。6日後
、右前足を切除し、この58後実験に用いた。この処理
により、右上腕及び右腋窩リンパ節への転移層モデルが
得られる。検体試料として 3H標識したコレステリル
リル−トを用いて作製した実施例8における本発明薬物
担体を用いた。対照試料としては、試験例2−1でも用
いた従来から知られる直径0.2μmの精製大豆油と卵
黄レシチンからなる脂肪乳剤に 3H標識したコレステ
リルリル−トを取り込ませたものを用いた。検体試料及
び対照試料を尾静脈内に投与し、60分後肢瘍転移の認
められる右上腕及び右腋窩リンパ節を摘出した。また、
非転移リンパ節として、左上腕及び左腋窩リンパ節も同
時に摘出し、各々の放射能濃度を測定した。
第6表に示すように、本発明薬物担体は、2倍以上の高
濃度で腫瘍部に移行した。対照試料には、このような高
濃度の選択的移行は認められなかった。
試験例2−8
腫瘍部位への移行性を確認する試験を行った。
5−1801!瘍細胞をddY系雄性マウス(体重約2
58)の腹部皮下に106個移植した。6日後、腫瘍の
直径が約legとなり実験に供した。
検体試料として 3Hfi識したコレステリルリル−ト
を用いて作製した実施例8における本発明薬物担体を用
いた。対照試料として従来から知られる直径0.2μの
大豆油と卵黄レシチンからなる脂肪乳剤に3H標識した
コレステリルリル−トを取り込ませたものを用いた。
検体試料及び対照試料を尾静脈内に投与し、15分、1
時間及び24時間後にllff1瘍を摘出し、放射能濃
度を測定した。
第7表に示すように、本発明薬物担体は、各時間におい
て対照試料の3倍程度の高濃度で腫瘍部に移行した。
表示は(投与量の%/g、平均上標準偏差)試験例2−
9
コレステリルリル−トを核とした本発明薬物担体の体内
安定性を確認する目的で実施例5で得た本発明薬物担体
を検体試料とし、実施例4で得た本発明薬物担体を比較
用試料としてそれぞれラットに静脈内投与した後の血中
濃度推移を検討した。各々の試料は、3H標識デキサメ
タシンパルミチン酸エステルを用いて作製したものを用
いた。
第4図に検体試料及び対照試料をデキサメタシン換算で
0.05mg/kg の投与量でSD系雄性ラット(
体重約250g )の尾静脈に静脈内投与したときの血
漿中捻放射能の推移をデキサメタシン換算で示した。検
体試料は比較用試料に比べ更に緩やかに血漿中より消失
した0分布相における消失半減期は、それぞれ21.6
分、及び11.5分である。
試験例2−10
実施例3、実施例4、及び実施例5で得た検体試料およ
び試験例2−1で用いた対照試料をそれぞれラットの血
漿と混合しその安定性について検討した。血漿中での試
料の濃度は、デキサメタシン換算で23μg/ml
とした。第8表に示すように、90分間37℃でインキ
ュベートした後の未変化体 (デキサメタシンパルミチ
ン酸エステル)の残存量、すなわち血漿中での安定性は
対照試料に比べ本発明薬物担体が優れることが明確であ
る。
加えて、本発明薬物担体の核にコレステリルリル−トを
用いるとその含量に依存して安定性が増すことも確かめ
られた。
試験例2−11
ddY系マウス(体重約30g)を用いてベンドパルビ
タール麻酔下、被検製剤を点眼後に眼球中の薬物濃度を
測定し、眼球への移行性を検討した。
被検製剤は、以下の4つである。
検体試料−(1) 抗炎症薬であるグアイアズレンを含
有する実施例1で得た本発明薬物担体。
検体試料−(2) 抗炎症薬であるグアイアズレンを含
有する実施例2で得た本発明薬物担体。
対照試料−(1) 従来技術である直径0.2μmの大
豆油と卵黄レシチンからなる脂肪乳剤にグアイアズレン
を取り込ませたもの。
対照試料−(2) 従来技術である直径0.2μmの大
豆油と卵黄レシチンからなる脂肪乳剤にグアイアズレン
の水溶性誘導体であるアズレンスルホン酸ナトリウムを
混合熔解させたもの。
用量はグアイアズレン換算で5μg/眼とした。
点眼後、一定時間で眼球を摘出し、生理食塩水で素早く
洗浄後、ホモジナイズし、高速液体クロマトグラフィー
により薬物を定量した。
眼球中薬物濃度推移を、第5図に示す。検体試料はいず
れも対照試料より良好な眼球移行を示し、本発明薬物担
体を用いた場合には、眼球への薬物移行が改善されるこ
とが明白である。
試験例2−12
実施例1で得たグアイアズレンを含有する薬物担体を検
体試料とし、グアイアズレンの水溶性誘導体アズレンス
ルホン酸ナトリウムを対照試料として、日本白色家兎(
体重約3kg >に点眼し、前房水中への薬物移行を検
討した。点眼後30分で、前房水を採取し、薬物濃度を
測定した。結果を第9表に示す。本発明薬物担体を用い
た場合にのみ前房水中への薬物移行が認められた。
試験例2−13
実施例6で得た抗ヒスタミン剤であるジフェンヒドラミ
ンを含有する本発明薬物担体を検体試料とし、塩酸ジフ
ェンヒドラミン生理食塩液溶液を対照試料として、ヒス
タミン皮肉投与により誘発される血管透過性の元通に対
する抑制作用について検討した。
SD系雄性ラット(体重的300g )に検体試料また
は対照試料を静脈内投与し、一定時間後エバンスブルー
10mgを静脈内投与すると共に腹部皮肉に塩酸ヒスタ
ミン(1μg150μl)を注入した。
さらに30分後、皮肉に漏出したエバンスブルーを定量
するため皮膚を剥離した。濃塩酸3m+1で皮膚を可溶
化した後、1θ%塩化ベンザルコニウム3mlヲ加え、
クロロホルム5+slでエバンスブルーヲ抽出した。ク
ロロホルム層の620nm の吸光度より皮肉に漏出
したエバンスブルー量を求めた。
第6図は、両試料の投与量を、ジフェンヒドラミン換算
で2a+g/kgとし、投与後15分、30分、120
分後にヒスタミンを皮肉に注入して得た血管透過性抑制
効果の時間的変化を示している。検体試料は、投与後1
5分で既に最大効果を示し、2時間までその効果は持続
した。一方、対照試料は検体試料に比べて抑制率は低く
、投与後30分で最大効果を示しその後低下した。投与
後2時間では、検体試料が対照試料の3倍以上の血管透
過性抑制効果を示した。これより、検体試料は、薬物効
果の増強のみならず、薬物作用の持続化にも効果を有す
ることが示された。
第7図は、試料投与30分で得た血管透過性の抑制効果
の用量作用曲線を示している。検体試料は、対照試料に
比べ血管透過性抑制効果に優れることが明確である。The present invention will be explained in more detail below with reference to Examples relating to the production of the drug carrier of the present invention, but it is clear that the present invention is not limited thereto. Example 1 To 27 mg of triolein, 38 mg of egg yolk lecithin and 10 g of guaiazulene (anti-inflammatory agent) were added, and 10 ml of physiological saline was added thereto.
) and subjected to ultrasonic treatment for 60 minutes under water cooling.The resulting drug carrier containing guaiazulene is blue and clear. The average particle diameter of this product measured by a light scattering particle diameter measuring device was 26.4 n-. Further, when morphologically observed using an electron microscope, it was recognized as uniform spherical ultrafine particles. Lipid bilayer membranes like liposomes were not observed. In addition, 100% passes through a 0.2 μ-filtration membrane,
It was found that it did not contain particles larger than 0.2 μm. Example 2 Egg yolk lecithin 2.5 mg and guaiazulene 10 mg
10 ml of physiological saline is added to this and subjected to ultrasonic treatment for 60 minutes under water cooling using a probe-type ultrasonic homogenizer (Pranson Sophia Model 185) to produce a drug carrier containing guaiazulene. The average particle diameter measured by a light scattering particle diameter measuring device is 48.4n.
It was also found that 100% of the particles passed through a 0.2μ filtration membrane and did not contain any particles larger than 0.2μ. Example 3 Triolein 10hg and egg yolk lecithin 100+sg
Add 4 mg of a compound (dexamethacin palmitate) in which a fatty acid is chemically bonded to dexamethacin (anti-inflammatory agent), add 10+ml of a 0.24yI glycerin aqueous solution, and use a probe-type ultrasonic homogenizer (Planson Sony). Fire model 185)
The resulting drug carrier containing dexamethacin palmitate is slightly bluish-white and clear. The average particle diameter of this product measured by a light scattering particle diameter measuring device is 29.9n+s
Met. In addition, 100% passes through a 0.2 μm filtration membrane,
It was found that it did not contain particles larger than 0.2 μm. Example 4 80 mg of triolein and 20 m of cholesteryl
After adding g, egg yolk lecithin 100+ag and dexamethacin palmitate 4n+g, a 0.21 aqueous glycerin solution 10-1 was added thereto and water-cooled using a probe-type ultrasonic homogenizer (Pranson Sonifier Model 185). Below, the drug carrier containing dexamethacin palmitate produced by ultrasonication for 60 minutes is slightly pale and clear. The average particle diameter of this product measured by a light scattering particle diameter measuring device was 30.6 nm. It was also found that 100% of the particles passed through a 0.2 μm filtration membrane and did not contain any particles larger than 0.2 μm. Example 5 Cholesteryl Rylate 10100l1 Egg Yolk Lecithin 10
0+ag and 4 mg of dexamethacin palmitate were added, 10 ml of 0.24 fl of a glycerin aqueous solution was added thereto, and the mixture was heated to 60°C for 60 minutes using a probe-type ultrasonic homogenizer (Planson Sonifier Model 185). Upon ultrasonication, the resulting drug carrier containing dexamethacin palmitate is slightly pale and clear. The average particle diameter of this product measured by a light scattering particle diameter measuring device was 22.
It was 7 nm. It was found that 100% of the 0.2 μm filtration membrane was used and did not contain any particles larger than 0.2 μm. Example 6 Triolein 100mg and egg yolk lecithin 100a+
g. and diphenhydramine (antihistamine) 10a+
g, and to this add 0.24M glycerin aqueous solution 1
Add 0a+1 and perform ultrasonic treatment for 60 minutes under water cooling using a probe-type ultrasonic homogenizer (Planson Sonifier Model 185). The resulting drug carrier containing diphenhydramine is slightly pale and clear. . The average particle diameter of this product was determined by a light scattering particle diameter measuring device to be 31.6 nm. Also, 0.2μ
It was found that 100% of the sample passed through the M filtration membrane and did not contain particles larger than 0.2 μm. Example 7 100mg of triolein and 100mg of egg yolk lecithin
Add to this 0.24? t glycerin aqueous solution 1
0+nl is added and subjected to ultrasonication for 60 minutes under water cooling using a probe-type ultrasonic homogenizer (Planson Sonifier Model 185). The resulting drug carrier is slightly pale and clear. The average particle diameter of this product measured by a light scattering particle diameter measuring device was 47.2 nm. In addition, 100% filtration membrane of 0.2μ section is used.
It was found that it did not contain particles larger than 0.2 μm. Compound (vinblastine balmitate ester) in which fatty acids are chemically bonded to vinblastine (anticancer drug) 50
0 μg was added to the drug carrier obtained above and gently mixed and stirred for 6 hours to incorporate the drug into the drug carrier. In this way, a drug carrier containing a drug was obtained. Adding 500 μg of a compound (5-fluorouracil palmitate) in which a fatty acid is chemically bonded to 5-fluorouracil (anticancer drug) to the drug carrier obtained above,
The mixture was gently mixed and stirred for 6 hours to incorporate the drug into the drug carrier. In this way, a drug carrier containing a drug was obtained. 500 μg of a compound (cytarabine levulinic acid ester) in which fatty acids are chemically bonded to cytarabine (anticancer drug),
The mixture was added to the drug carrier obtained above and gently mixed and stirred for 6 hours to incorporate the drug into the drug carrier. In this way, a drug carrier containing a drug was obtained. Example 8 Triolein 80mg, cholesteryl) 20
+++g, and 0.2 to 100mg of egg yolk lecithin
Add 10 ml of 4M aqueous glycerin solution and perform ultrasonic treatment for 60 minutes under water cooling using a probe-type ultrasonic homogenizer (Planson Sonifier Model 185). The resulting drug carrier is slightly pale and clear. The average particle diameter of this product measured by a light scattering particle diameter measuring device was 19.1 nm. Figure 1 shows the analysis results. It was also found that 100% of the particles passed through a 0.2 μm filtration membrane and did not contain any particles larger than 0.2 μm. Example 9 Add 20 mg of egg yolk lecithin to 20 ttrg of refined soybean oil, and add 10 ml of 0.24 M glycerin aqueous solution to this.
using a probe-type ultrasonic homogenizer (Pranson Sonifier Model 185) under water cooling.
Sonicate for 60 minutes. The resulting drug carrier is slightly pale and clear. The average particle diameter of this product measured by a light scattering particle diameter measuring device was 16.1 nm. Also,
100% passes through 0.2 μm filtration membrane, 0.2
It was found that it did not contain particles larger than μm. Further, a drug carrier was produced using 40 mg of purified soybean oil in the same manner as above. The resulting drug carrier is slightly pale and clear. The average particle diameter of this product measured by a light scattering particle diameter measuring device was 37.7n+a. In addition, 100% passes through a 0.2 μm filtration membrane,
It was found that it did not contain particles larger than 0.2 μm. Example 1O 10 g of egg yolk lecithin was added to 10 g of soybean oil, and 0.0 g of lecithin was added to 10 g of soybean oil.
A 24M aqueous glycerin solution at 1°C is added and emulsified using a microfluidizer. The drug carrier produced is 0.2
It was found that 100% of the sample passed through the μl filtration membrane and contained no particles larger than 0.2 μm. [Stability test of the drug carrier of the present invention] Test example 1-1 The sample obtained in Example 1 was sealed in a brown ampoule with a capacity of 1 ml together with nitrogen gas, and subjected to an abuse test at 60°C for 4 weeks according to a conventional method. went. The survival rate of guaiazulene is 98.3
% or more, and it was confirmed that the drug carrier of the present invention has an effect on drug stability. Test Example 1-2 The samples obtained in Examples 1, 3, and 4 were sealed together with nitrogen gas in a brown ampoule with a capacity of 1 ml. After sterilizing this with high pressure steam in an autoclave,
When the particle size of the sample was measured using a light scattering particle size measuring device, there was no significant difference from before treatment, and no aggregation or increase in particle size was observed. Further, when this product was stored at 4°C for 6 months, no changes such as aggregation were observed. Test Example 1-3 The sample obtained in Example 3 above was freeze-dried according to a conventional method. Then, after adding distilled water for injection and stirring to restore the sample, the particle size of the sample was measured using a light scattering particle size measuring device, and the average particle size was 28.3 nm, and no significant aggregation or increase in particle size was observed. It was dispersed evenly. [Test of usefulness of the present invention] Test Example 2-1 A drug carrier of the present invention containing 3H-labeled dexamethacin palmitate prepared in the same manner as in Example 3 was used as a test sample. As a control sample, a conventional technique with a diameter of 0.2
A μm fat emulsion was used. This control sample is 'HIKf
i Dexamethacin palmitate 4 tags
100n+g of refined soybean oil, 12mg of egg yolk lecithin and 0.
It was emulsified by adding 10n+1 of a 24M glycerin aqueous solution. The changes in blood concentration after intravenous administration of test samples and control samples to rats were investigated. Figure 2 shows the change in plasma radioactivity of dexamethacin when the test sample and control sample were intravenously administered into the tail vein of male SD rats (weight 210 g) at a dose of 0.05+ag/kg in terms of dexamethacin. Shown in terms of conversion. The control sample disappeared from the plasma quickly, but the test sample disappeared from the plasma slowly, and the elimination half-lives in the distribution phase were 10.5 minutes and 5.5 minutes, respectively. Test Example 2-2 A drug carrier of the present invention containing 3H-labeled dexamethacin palmitate prepared in the same manner as in Example 4 was used as a test sample and the same control sample as used in Test Example 2-1 was used to test carrageenan. The drug transfer to the inflammation site due to edema was compared between the specimen sample and the control sample. 0 on one side of SD male rat (weight 195g)
.. 0.1 ml of 5% λ-carrageenan was subcutaneously administered to create carrageenan edema. Two hours after the administration of carrageenan, the test sample and control sample were intravenously administered into the tail vein at a dose of 0.5 mg/kg in terms of dexamethacin. Sixty minutes after intravenous administration, blood was collected from the abdominal aorta to obtain plasma, and the inflamed leg and opposite leg (control leg) were amputated at the ankle joint. The radioactivity of each sample was measured after processing with a sample combustion device. In Table 1, compared to the control sample, a larger amount of drug was transferred to the inflamed area (edematous area) in the specimen sample, and a strong tendency to accumulate in the inflamed area was observed. In the edematous area caused by inflammation, a drug concentration 5.7 times that of the control sample was observed. Test Example 2-3 Table 2 shows a comparative study of drug migration into the pleura and into major tissues in a raft pleuritis model using the same specimen sample and control sample used in Test Example 2-2 above. It is. 2% in the thoracic cavity of SD male rats (weight 300 g).
1 ml of λ-carrageenan O was injected. 2.5 hours after the administration of carrageenan, the test sample and control sample were intravenously administered into the tail vein at a dose of 1.25+mg/kg in terms of dexamethacin. 30 minutes after intravenous administration, blood was removed from the abdominal aorta, and the pleura was washed out with physiological saline and then removed for 10 m.
1 and radioactivity was measured. At the same time, major organs were also removed, and the radioactivity of each was measured after processing with a sample combustion device. Table 2. Transfer to the inflammation site and major tissues is the average value converted to dexamethacin. gender was recognized. 3.9 times more drug was found in the swollen water than in the control sample. In terms of distribution to major organs, the sample showed extremely low levels of migration to tissues with developed sperm endothelial system, such as the liver and pancreas. Test Example 2-4 The same test sample and control sample used in Test Example 2-2 above were administered intravenously to BALB/C male mice (body weight approximately 25 g), and 30 minutes later The concentration of malted rice and the metabolite dexamethacin concentration were measured. The dose was 5 mg/kg in terms of dexamethacin. Table 3 shows the concentrations of the unchanged substance (dexamethacin balmitate, concentration expressed in terms of dexamethacin) and metabolite (dexamethacin) after they were separated and quantified by thin layer chromatography. In the case of the specimen, the plasma concentration was high and the distribution to the liver was low. In addition, most of it was present in the unchanged form in the blood sputum. When the drug carrier of the present invention is used, the effect of maintaining the blood concentration of the drug and suppressing its uptake into the reticuloendothelial system is obvious. The display is (average standard deviation) (see next page) Test Example 2-5 Pharmacological effects were determined using carrageenan edema suppression as an indicator for the same test sample and control sample used in Test Example 2-2, as well as dexamethacin phosphate saline solution. It was investigated. SD male rats (weighing approximately 160 g) were limited to one side.
λ-carrageenan (0.5x, 0.1+ml) was administered subcutaneously, and 30 minutes later, the test sample, control sample, and dexamethacin phosphate were administered intravenously through the tail vein. Physiological saline was administered to the control group. A constant volume was measured in a conventional manner before and 5 hours after administration of carrageenan to determine the edema suppression rate. FIG. 3 shows the dose-response curve (expressed in terms of dexamethacine). The 50% edema-inhibiting doses (EDs) are shown in Table 4. It is clear that the specimen sample has about twice the anti-inflammatory activity compared to the other two samples even in this type of inflammation, which was not improved by the prior art control sample. That is, the effect of the drug carrier of the present invention was confirmed as an enhancement effect of the drug effect. This is clearly due to the efficient transfer of the drug to the lesion by using the drug carrier of the present invention. The posterior granuloma, thymus and adrenal gland were removed and their weights were measured. From Table 5, it can be seen that the specimen sample clearly has a stronger granuloma formation inhibiting effect (and less atrophic effect on the thymus and adrenal glands) than the control sample and dexamethacin phosphate.In other words, the specimen sample has a pharmacological effect. It was shown that there were strong and few side effects.Test Example 2-6 The pharmacological effects were evaluated using carrageenan granuloma inhibition as an index for the same specimen sample and control sample used in Test Example 2-2, and the dexamethacin phosphate saline solution. Also, tfi
lil and adrenal gland weight were examined. Subcutaneously on the back of SD male rats (weighing approximately 160 g).
Lambda-carrageenan (2.0x, 4.0a+1) was administered subcutaneously, and from 5 days later, each sample was administered once a day for 3 days in total.
It was administered intravenously through the ileotail vein. The drug dose was 0.05 mg/kg per dose in terms of dexamethacin. Physiological saline was administered to the control group. The 8-day display is (average value above standard deviation) Test Example 2-7 A test was conducted to confirm the migration to the tumor site. P388 leukemia cells were transferred to CDF1 male mice (body weight approx.
108 pieces were transplanted subcutaneously to the heel of the right forefoot of 5g). After 6 days, the right front paw was excised and used for this 58-day experiment. This process provides a metastatic layer model to the right upper arm and right axillary lymph nodes. The drug carrier of the present invention in Example 8, which was prepared using 3H-labeled cholesteryl phosphate, was used as a test sample. As a control sample, a conventionally known fat emulsion consisting of purified soybean oil and egg yolk lecithin with a diameter of 0.2 μm, which was also used in Test Example 2-1, was used, in which 3H-labeled cholesteryl lylate was incorporated. The specimen sample and the control sample were administered into the tail vein, and the right upper arm and right axillary lymph nodes in which hindlimb tumor metastasis was observed were removed for 60 minutes. Also,
As non-metastatic lymph nodes, the left upper arm and left axillary lymph nodes were also removed at the same time, and the radioactivity concentration of each was measured. As shown in Table 6, the drug carrier of the present invention migrated to the tumor site at a concentration more than twice as high. No such high concentration of selective migration was observed in the control sample. Test Example 2-8 A test was conducted to confirm migration to tumor sites. 5-1801! Tumor cells were transferred to ddY male mice (body weight approx.
106 cells were transplanted subcutaneously into the abdomen of 58). After 6 days, the tumor had a diameter of about 1 leg and was used for experiments. The drug carrier of the present invention in Example 8, which was prepared using cholesteryl chloride recognized by 3Hfi, was used as a test sample. As a control sample, a conventionally known fat emulsion consisting of soybean oil and egg yolk lecithin with a diameter of 0.2 microns was used, in which 3H-labeled cholesteryl lylate was incorporated. The test sample and control sample were administered into the tail vein for 15 minutes, 1
The llff1 tumor was excised after 3 hours and 24 hours, and the radioactivity concentration was measured. As shown in Table 7, the drug carrier of the present invention migrated to the tumor site at a concentration three times higher than that of the control sample at each time point. The display is (% of dose/g, standard deviation above the mean) Test Example 2-
9 In order to confirm the in-vivo stability of the drug carrier of the present invention having cholesteryl lylate as its core, the drug carrier of the present invention obtained in Example 5 was used as a test sample, and the drug carrier of the present invention obtained in Example 4 was used as a comparative sample. The changes in blood concentration after intravenous administration of each sample to rats were investigated. Each sample was prepared using 3H-labeled dexamethacin palmitate. Figure 4 shows that test samples and control samples were administered to SD male rats at a dose of 0.05 mg/kg (calculated as dexamethacin).
The change in plasma radioactivity when administered intravenously into the tail vein of a body weight of approximately 250 g (body weight approximately 250 g) is shown in terms of dexamethacin. The specimen sample disappeared from plasma more slowly than the comparison sample, and the elimination half-life in the 0 distribution phase was 21.6.
minutes, and 11.5 minutes. Test Example 2-10 The specimen samples obtained in Examples 3, 4, and 5 and the control sample used in Test Example 2-1 were mixed with rat plasma, and their stability was examined. The concentration of the sample in plasma was 23 μg/ml in terms of dexamethacin.
And so. As shown in Table 8, the drug carrier of the present invention is superior to the control sample in terms of the remaining amount of unchanged drug (dexamethacin palmitate ester) after incubation at 37°C for 90 minutes, that is, its stability in plasma. That is clear. In addition, it was also confirmed that when cholesteryl lyte is used as the core of the drug carrier of the present invention, the stability increases depending on its content. Test Example 2-11 Using ddY mice (body weight: approximately 30 g), the test formulation was instilled into the eyes of ddY mice under anesthesia with bendoparbital, and the drug concentration in the eyes was measured to examine the transferability to the eyes. The following four formulations were tested. Specimen Sample-(1) The drug carrier of the present invention obtained in Example 1 containing guaiazulene, an anti-inflammatory drug. Specimen Sample-(2) The drug carrier of the present invention obtained in Example 2 containing guaiazulene, which is an anti-inflammatory drug. Control Sample - (1) Guaiazulene was incorporated into a conventional fat emulsion consisting of soybean oil and egg yolk lecithin with a diameter of 0.2 μm. Control sample (2) A conventional fat emulsion consisting of soybean oil and egg yolk lecithin with a diameter of 0.2 μm was mixed and dissolved with sodium azulene sulfonate, which is a water-soluble derivative of guaiazulene. The dose was 5 μg/eye in terms of guaiazulene. After instillation, the eyeballs were removed after a certain period of time, quickly washed with physiological saline, homogenized, and the drug was quantified by high performance liquid chromatography. The changes in drug concentration in the eyeballs are shown in Figure 5. All of the test samples showed better ocular transfer than the control sample, and it is clear that drug transfer to the eyeballs is improved when the drug carrier of the present invention is used. Test Example 2-12 The drug carrier containing guaiazulene obtained in Example 1 was used as a test sample, and the water-soluble derivative of guaiazulene, sodium azulene sulfonate, was used as a control sample.
The eye drops were applied to patients weighing approximately 3 kg, and drug transfer into the anterior aqueous humor was examined. Thirty minutes after instillation, the anterior aqueous humor was collected and the drug concentration was measured. The results are shown in Table 9. Drug migration into the anterior aqueous humor was observed only when the drug carrier of the present invention was used. Test Example 2-13 The drug carrier of the present invention containing the antihistamine diphenhydramine obtained in Example 6 was used as a test sample, and the physiological saline solution of diphenhydramine hydrochloride was used as a control sample to determine the cause of vascular permeability induced by subclinical administration of histamine. We investigated its inhibitory effect on phlegm. A test sample or a control sample was intravenously administered to SD male rats (weighing 300 g), and after a certain period of time, Evans blue (10 mg) was intravenously administered and histamine hydrochloride (1 μg, 150 μl) was injected into the abdomen. After an additional 30 minutes, the skin was peeled off to quantify the Evans blue that had leaked out. After solubilizing the skin with 3 m+1 concentrated hydrochloric acid, 3 ml of 1θ% benzalkonium chloride was added.
Evans blue was extracted with chloroform 5+sl. The amount of Evans blue leaked was determined from the absorbance of the chloroform layer at 620 nm. Figure 6 shows that the dose of both samples was 2a+g/kg in terms of diphenhydramine, and the doses were 15 minutes, 30 minutes, and 120 minutes after administration.
It shows the temporal change in the vascular permeability suppressing effect obtained by ironically injecting histamine after 1 minute. The specimen sample is 1 after administration.
The maximum effect was already shown in 5 minutes and the effect lasted for up to 2 hours. On the other hand, the inhibition rate of the control sample was lower than that of the test sample, with the maximum effect occurring 30 minutes after administration and decreasing thereafter. Two hours after administration, the test sample showed a vascular permeability suppressing effect three times or more greater than that of the control sample. This indicates that the specimen sample is effective not only in enhancing the drug effect but also in prolonging the drug effect. FIG. 7 shows a dose-response curve for the suppressive effect on vascular permeability obtained 30 minutes after sample administration. It is clear that the specimen sample has a superior vascular permeability suppressing effect compared to the control sample.
第1図は、実施例8で製造した本発明薬物担体の粒子径
を、光散乱粒子径測定装置で測定した結果を示す。縦軸
は粒子数、横軸は粒子径を対数目盛りで表している。
第2図は、試験例2−1で検討した検体試料と対照試料
をラットに静脈内投与したときの血漿中総放射能の推移
を表す、Il軸は、放射能より換算したデキサメタシン
濃度(ng/ml )を、 横軸は投与後の経過時間(
時間)を表す。
・印線は検体試料を、Q印線は対照試料をそれぞれ表す
。
第3図は、試験例2−2で検討した検体試料と対照試料
をラットに静脈内投与したときの抗炎症活性をカラゲニ
ン浮腫の抑制率を指標にして得た用量作用曲線である。
縦軸はカラゲニン浮腫の抑制率を%表示で、横軸は薬物
投与量をデキサメタシン換算で対数目盛りで表す。
・印線は検体試料を、Δ印線はリン酸デキサメタシンを
、O印線は対照試料をそれぞれ表す。
第4図は、試験例2−9で検討した検体試料と比較用試
料をラットに静脈内投与したときの血漿中総放射能の推
移を表す。縦軸は、放射能より換算したデキサメタシン
濃度(ng/ml )を、 横軸は投与後の経過時間(
時間)を表す、ム印線は検体試料を、・印線は比較用試
料をそれぞれ表す。
第5図は、試験例2−11で検討した2種の検体試料と
21!の対照試料をマウスに点眼した後の眼球中への薬
物移行量を表す、縦軸は、眼球中の薬物濃度(ng/g
、グアイアズレン換算)を、横軸は点眼後の時間経過(
時間)を表す、ム印線は、検体試料−(1)を、Δ印線
は検体試料−(2)を、■印線は対照試料−(1)を、
○印線は対照試料−(2)をそれぞれ表す。
第6図は、試験例2−13で検討した検体試料と対照試
料をラットに投与したときの血管透過性抑制効果の時間
推移を示したものである。縦軸は、血管、透過性の抑制
率をパーセント表示で、横軸は、試料投与後の時間経過
(時間)を表す。
・印線は検体試料を、○印線は対照試料をそれぞれ表す
。
第7図は、試験例2−13で検討した検体試料と対照試
料をラットに投与したときの血管透過性抑制効果の用量
作用曲線を示したものである。縦軸は、血管透過性の抑
制率をパーセント表示で、横軸は薬物投与量を塩酸ジフ
ェンヒドラミン換算で対数目盛りで表す。
・印線は検体試料を、○印線は対照試料をそれぞれ表す
。FIG. 1 shows the results of measuring the particle size of the drug carrier of the present invention produced in Example 8 using a light scattering particle size measuring device. The vertical axis represents the number of particles, and the horizontal axis represents the particle diameter on a logarithmic scale. Figure 2 shows the change in plasma total radioactivity when the test sample and control sample studied in Test Example 2-1 were intravenously administered to rats. The Il axis is the dexamethacin concentration (ng /ml), and the horizontal axis is the elapsed time after administration (
time). - The marked line represents the specimen sample, and the Q marked line represents the control sample. FIG. 3 is a dose-response curve obtained by using the inhibition rate of carrageenan edema as an index of the anti-inflammatory activity when the specimen sample and control sample examined in Test Example 2-2 were intravenously administered to rats. The vertical axis represents the suppression rate of carrageenan edema in %, and the horizontal axis represents the drug dose in terms of dexamethacin on a logarithmic scale. - The marked line represents the specimen sample, the Δ marked line represents dexamethacin phosphate, and the O marked line represents the control sample. FIG. 4 shows the change in plasma total radioactivity when the specimen sample and comparative sample examined in Test Example 2-9 were intravenously administered to rats. The vertical axis is the dexamethacin concentration (ng/ml) calculated from radioactivity, and the horizontal axis is the elapsed time after administration (
The line marked with ``mu'' represents the specimen sample, and the line marked with * represents the sample for comparison. Figure 5 shows the two types of specimen samples examined in Test Example 2-11 and 21! The vertical axis represents the amount of drug transferred into the eyeballs after instilling a control sample into the eyes of mice. The vertical axis represents the drug concentration in the eyes (ng/g
, guaiazulene equivalent), and the horizontal axis is the time elapsed after instillation (
The mu-marked line represents the specimen sample-(1), the Δ-marked line represents the specimen sample-(2), the ■-marked line represents the control sample-(1),
The lines marked with ○ each represent the control sample-(2). FIG. 6 shows the time course of the vascular permeability suppressing effect when the specimen sample and control sample examined in Test Example 2-13 were administered to rats. The vertical axis represents the inhibition rate of blood vessels and permeability as a percentage, and the horizontal axis represents the passage of time (hours) after sample administration. - The marked line represents the specimen sample, and the circle mark represents the control sample. FIG. 7 shows a dose-response curve of the vascular permeability suppressing effect when the specimen sample and control sample examined in Test Example 2-13 were administered to rats. The vertical axis represents the inhibition rate of vascular permeability as a percentage, and the horizontal axis represents the drug dose in terms of diphenhydramine hydrochloride on a logarithmic scale. - The marked line represents the specimen sample, and the circle mark represents the control sample.
Claims (7)
、薬物を含有し平均粒子径が200nm未満である薬物
担体。(1) A drug carrier in the form of a fat emulsion that contains a drug and has an average particle diameter of less than 200 nm.
において、 [1]脂肪乳剤の核を構成する物質が、単純脂質、誘導
脂質、若しくは薬物そのもの自体、又はこれらの混合物
であり、薬物担体中のその含有比率が30〜85%であ
り、 [2]脂肪乳剤の表層を構成する物質が、複合脂質、誘
導脂質、若しくは薬物そのもの自体、又はこれらの混合
物であり、薬物担体中のその含有比率が15〜70%で
あり、 上記[1]と[2]の性質を同時に有することを特徴と
する特許請求の範囲第1項記載の薬物担体。(2) In a fat emulsion consisting of a core substance and a surface layer substance, [1] The substance constituting the core of the fat emulsion is a simple lipid, a derived lipid, the drug itself, or a mixture thereof; The content ratio in the carrier is 30 to 85%; [2] The substance constituting the surface layer of the fat emulsion is a complex lipid, a derived lipid, the drug itself, or a mixture thereof; The drug carrier according to claim 1, which has a content ratio of 15 to 70% and simultaneously has the properties [1] and [2] above.
これらの混合物である特許請求の範囲第2項の薬物担体
。(3) The drug carrier according to claim 2, wherein the simple lipid is a neutral lipid, a styrene ester, or a mixture thereof.
物である特許請求の範囲第2項の薬物担体。(4) The drug carrier according to claim 2, wherein the complex lipid is a phospholipid, a glycolipid, or a mixture thereof.
又はこれら2つ以上の混合物である特許請求の範囲第2
項の薬物担体。(5) The derived lipid is a fatty acid, a higher alcohol, a hydrocarbon,
or a mixture of two or more of these.
drug carrier.
物担体構成成分との混合ミセル形成、又は薬物担体構成
成分との化学的結合である特許請求の範囲第2項の薬物
担体。(6) The drug carrier according to claim 2, wherein the drug is contained in the drug carrier in the form of dispersion, dissolution, mixed micelle formation with the drug carrier components, or chemical bonding with the drug carrier components.
とする脂肪乳剤。(7) A fat emulsion characterized by not containing particles with a diameter of 200 nm or more.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP24952688A JPH0798740B2 (en) | 1987-10-28 | 1988-10-03 | Drug carrier |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62-272770 | 1987-10-28 | ||
JP27277087 | 1987-10-28 | ||
JP24952688A JPH0798740B2 (en) | 1987-10-28 | 1988-10-03 | Drug carrier |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH02203A true JPH02203A (en) | 1990-01-05 |
JPH0798740B2 JPH0798740B2 (en) | 1995-10-25 |
Family
ID=26539339
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP24952688A Expired - Fee Related JPH0798740B2 (en) | 1987-10-28 | 1988-10-03 | Drug carrier |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0798740B2 (en) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01143826A (en) * | 1987-11-30 | 1989-06-06 | Taisho Pharmaceut Co Ltd | Fat emulsion of fine particle |
JPH01249716A (en) * | 1988-03-29 | 1989-10-05 | Taisho Pharmaceut Co Ltd | Fatty emulsion of fine particle |
JPH02167217A (en) * | 1988-09-29 | 1990-06-27 | Shiseido Co Ltd | Emulsified composition |
WO1992007551A1 (en) * | 1990-11-06 | 1992-05-14 | Nippon Shinyaku Co., Ltd. | Process for producing fat emulsion |
WO1992007552A1 (en) * | 1990-11-06 | 1992-05-14 | Nippon Shinyaku Co., Ltd. | Lyophilized preparation and production thereof |
JP2616240B2 (en) * | 1990-11-06 | 1997-06-04 | 日本新薬株式会社 | Production method of fat emulsion |
JPH10504021A (en) * | 1994-05-16 | 1998-04-14 | ザ ボード オブ リージェンツ オブ ザ ユニヴァーシティ オブ ミシガン | Hepatocyte-selective oil-in-water emulsion |
WO1998037869A1 (en) * | 1997-02-27 | 1998-09-03 | Nippon Shinyaku Co., Ltd. | Fat emulsion for oral administration |
JP2007262088A (en) * | 1998-08-31 | 2007-10-11 | Nipro Corp | Nutrition transfusion formulation |
KR100774515B1 (en) * | 2006-06-20 | 2007-11-08 | 포항공과대학교 산학협력단 | Localization method of autonomous mobile robot using grid-based map |
JP2009501802A (en) * | 2005-07-18 | 2009-01-22 | ユニバーシティ オブ マサチューセッツ ロウエル | Compositions and methods for making and using nanoemulsions |
JP2010270023A (en) * | 2009-05-20 | 2010-12-02 | Techno Guard Kk | Nonaqueous composition containing adipose particle holding medicament, and method for producing the same |
WO2012133554A1 (en) * | 2011-03-31 | 2012-10-04 | 富士フイルム株式会社 | Fat emulsion containing prostaglandin |
JP2012214431A (en) * | 2011-03-31 | 2012-11-08 | Fujifilm Corp | Fat emulsion containing prostaglandin |
JP2012214430A (en) * | 2011-03-31 | 2012-11-08 | Fujifilm Corp | Fat emulsion containing prostaglandin |
JP2014012737A (en) * | 2013-10-21 | 2014-01-23 | Techno Guard Kk | Nonaqueous composition containing adipose particle holding medicament, and method for producing the same |
US9724299B2 (en) | 2006-12-01 | 2017-08-08 | Anterios, Inc. | Amphiphilic entity nanoparticles |
US10016451B2 (en) | 2007-05-31 | 2018-07-10 | Anterios, Inc. | Nucleic acid nanoparticles and uses therefor |
US10532019B2 (en) | 2005-12-01 | 2020-01-14 | University Of Massachusetts Lowell | Botulinum nanoemulsions |
US10905637B2 (en) | 2006-12-01 | 2021-02-02 | Anterios, Inc. | Peptide nanoparticles and uses therefor |
US11311496B2 (en) | 2016-11-21 | 2022-04-26 | Eirion Therapeutics, Inc. | Transdermal delivery of large agents |
-
1988
- 1988-10-03 JP JP24952688A patent/JPH0798740B2/en not_active Expired - Fee Related
Cited By (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01143826A (en) * | 1987-11-30 | 1989-06-06 | Taisho Pharmaceut Co Ltd | Fat emulsion of fine particle |
JPH01249716A (en) * | 1988-03-29 | 1989-10-05 | Taisho Pharmaceut Co Ltd | Fatty emulsion of fine particle |
JPH02167217A (en) * | 1988-09-29 | 1990-06-27 | Shiseido Co Ltd | Emulsified composition |
WO1992007551A1 (en) * | 1990-11-06 | 1992-05-14 | Nippon Shinyaku Co., Ltd. | Process for producing fat emulsion |
WO1992007552A1 (en) * | 1990-11-06 | 1992-05-14 | Nippon Shinyaku Co., Ltd. | Lyophilized preparation and production thereof |
JP2616240B2 (en) * | 1990-11-06 | 1997-06-04 | 日本新薬株式会社 | Production method of fat emulsion |
JPH10504021A (en) * | 1994-05-16 | 1998-04-14 | ザ ボード オブ リージェンツ オブ ザ ユニヴァーシティ オブ ミシガン | Hepatocyte-selective oil-in-water emulsion |
WO1998037869A1 (en) * | 1997-02-27 | 1998-09-03 | Nippon Shinyaku Co., Ltd. | Fat emulsion for oral administration |
JP2007262088A (en) * | 1998-08-31 | 2007-10-11 | Nipro Corp | Nutrition transfusion formulation |
JP2009501802A (en) * | 2005-07-18 | 2009-01-22 | ユニバーシティ オブ マサチューセッツ ロウエル | Compositions and methods for making and using nanoemulsions |
JP2013028615A (en) * | 2005-07-18 | 2013-02-07 | Univ Of Massachusetts Lowell | Composition and method for manufacturing and using nanoemulsion |
US10016364B2 (en) | 2005-07-18 | 2018-07-10 | University Of Massachusetts Lowell | Compositions and methods for making and using nanoemulsions |
US10576034B2 (en) | 2005-12-01 | 2020-03-03 | University Of Massachusetts Lowell | Botulinum nanoemulsions |
US10532019B2 (en) | 2005-12-01 | 2020-01-14 | University Of Massachusetts Lowell | Botulinum nanoemulsions |
KR100774515B1 (en) * | 2006-06-20 | 2007-11-08 | 포항공과대학교 산학협력단 | Localization method of autonomous mobile robot using grid-based map |
US10905637B2 (en) | 2006-12-01 | 2021-02-02 | Anterios, Inc. | Peptide nanoparticles and uses therefor |
US10758485B2 (en) | 2006-12-01 | 2020-09-01 | Anterios, Inc. | Amphiphilic entity nanoparticles |
US10285941B2 (en) | 2006-12-01 | 2019-05-14 | Anterios, Inc. | Amphiphilic entity nanoparticles |
US9724299B2 (en) | 2006-12-01 | 2017-08-08 | Anterios, Inc. | Amphiphilic entity nanoparticles |
US10016451B2 (en) | 2007-05-31 | 2018-07-10 | Anterios, Inc. | Nucleic acid nanoparticles and uses therefor |
JP2010270023A (en) * | 2009-05-20 | 2010-12-02 | Techno Guard Kk | Nonaqueous composition containing adipose particle holding medicament, and method for producing the same |
JP2012214430A (en) * | 2011-03-31 | 2012-11-08 | Fujifilm Corp | Fat emulsion containing prostaglandin |
JP2012214431A (en) * | 2011-03-31 | 2012-11-08 | Fujifilm Corp | Fat emulsion containing prostaglandin |
WO2012133554A1 (en) * | 2011-03-31 | 2012-10-04 | 富士フイルム株式会社 | Fat emulsion containing prostaglandin |
JP2014012737A (en) * | 2013-10-21 | 2014-01-23 | Techno Guard Kk | Nonaqueous composition containing adipose particle holding medicament, and method for producing the same |
US11311496B2 (en) | 2016-11-21 | 2022-04-26 | Eirion Therapeutics, Inc. | Transdermal delivery of large agents |
Also Published As
Publication number | Publication date |
---|---|
JPH0798740B2 (en) | 1995-10-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA1333993C (en) | Drug carriers | |
US5651991A (en) | Drug carriers | |
JPH02203A (en) | Drug carrier | |
AU593014B2 (en) | Emulsion compositions for administration of sparingly water soluble ionizable hydrophobic drugs | |
JP2785981B2 (en) | Emulsion composition | |
JP4755742B2 (en) | Use of nano-dispersions in pharmaceutical final formulations | |
JPS609726B2 (en) | steroid preparations | |
Tamilvanan | Formulation of multifunctional oil-in-water nanosized emulsions for active and passive targeting of drugs to otherwise inaccessible internal organs of the human body | |
DE69426570T2 (en) | MICELLOUS FINE-PARTIAL PHARMACEUTICAL COMPOSITIONS | |
CN1706371B (en) | Efficient sword-like iris seed preparation and its preparation process | |
JP2844756B2 (en) | Fat emulsion | |
AU764413B2 (en) | A pharmaceutical composition comprising cyclosporin in a lipid carrier | |
JPH02167217A (en) | Emulsified composition | |
WO1991007973A1 (en) | Fat emulsion | |
JP3249583B2 (en) | Liposome preparation | |
JP3074732B2 (en) | Fat emulsion | |
KR100524700B1 (en) | Pharmaceutical compositions for Hyperlipidemia treatment using of Self Emulsifying drug delivery system | |
JP2616240B2 (en) | Production method of fat emulsion | |
JP2626247B2 (en) | Lyophilized formulation and manufacturing method | |
JPS61221114A (en) | Fat emulsion | |
CN110339164A (en) | Ketorolac ester derivative intravenous injection fatty emulsion, preparation method and application | |
CN107137351A (en) | A kind of Alprostadil emulsions parenteral solution of stabilization | |
JPH05139957A (en) | Fat emulsion containing phosphatidylserine as constituent component | |
JPH04108732A (en) | Paf antagonistic agent-containing fatty emulsion | |
JPH0489430A (en) | Hypotension maintaining agent |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |