TWI736577B - 5-胺基乙醯丙酸和其衍生物的鹽 - Google Patents
5-胺基乙醯丙酸和其衍生物的鹽 Download PDFInfo
- Publication number
- TWI736577B TWI736577B TW106102897A TW106102897A TWI736577B TW I736577 B TWI736577 B TW I736577B TW 106102897 A TW106102897 A TW 106102897A TW 106102897 A TW106102897 A TW 106102897A TW I736577 B TWI736577 B TW I736577B
- Authority
- TW
- Taiwan
- Prior art keywords
- trichloroacetate
- propionate
- salt
- acid
- salt compound
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title abstract description 93
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical class NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 title abstract description 48
- 229960002749 aminolevulinic acid Drugs 0.000 title abstract description 5
- -1 salt compound Chemical class 0.000 claims description 95
- 239000002253 acid Substances 0.000 claims description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 16
- YNJBWRMUSHSURL-UHFFFAOYSA-M trichloroacetate Chemical compound [O-]C(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-M 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 11
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 claims description 10
- 125000002528 4-isopropyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 9
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 67
- 238000009472 formulation Methods 0.000 abstract description 23
- 238000002428 photodynamic therapy Methods 0.000 abstract description 23
- 239000003504 photosensitizing agent Substances 0.000 abstract description 20
- 238000002360 preparation method Methods 0.000 abstract description 15
- 239000002537 cosmetic Substances 0.000 abstract description 10
- 238000003745 diagnosis Methods 0.000 abstract description 10
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 59
- 238000000034 method Methods 0.000 description 35
- 150000002148 esters Chemical class 0.000 description 29
- 238000011282 treatment Methods 0.000 description 28
- 239000000243 solution Substances 0.000 description 23
- 210000003491 skin Anatomy 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 125000004429 atom Chemical group 0.000 description 18
- 125000003118 aryl group Chemical group 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 229940120124 dichloroacetate Drugs 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- 208000002874 Acne Vulgaris Diseases 0.000 description 14
- 206010000496 acne Diseases 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 14
- 239000006071 cream Substances 0.000 description 14
- 125000000623 heterocyclic group Chemical group 0.000 description 14
- 239000003814 drug Substances 0.000 description 13
- 150000004032 porphyrins Chemical class 0.000 description 13
- QLMULGDHOCOFHT-UHFFFAOYSA-N 2-chloroacetic acid;propanoic acid Chemical compound CCC(O)=O.OC(=O)CCl QLMULGDHOCOFHT-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- 201000010099 disease Diseases 0.000 description 12
- 229940066528 trichloroacetate Drugs 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 239000002674 ointment Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 10
- 229950003776 protoporphyrin Drugs 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 239000000969 carrier Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 230000000699 topical effect Effects 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 125000002837 carbocyclic group Chemical group 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 239000002270 dispersing agent Substances 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- SAWDRMCVTORURM-UHFFFAOYSA-N C(CC)(=O)O.ClC(C(=O)O)(Cl)Cl Chemical compound C(CC)(=O)O.ClC(C(=O)O)(Cl)Cl SAWDRMCVTORURM-UHFFFAOYSA-N 0.000 description 6
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- 150000004665 fatty acids Chemical class 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 5
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 5
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 5
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 5
- 206010040880 Skin irritation Diseases 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- JXTHNDFMNIQAHM-UHFFFAOYSA-M dichloroacetate Chemical compound [O-]C(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-M 0.000 description 5
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 5
- 239000003456 ion exchange resin Substances 0.000 description 5
- 229920003303 ion-exchange polymer Polymers 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 230000035515 penetration Effects 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 235000019260 propionic acid Nutrition 0.000 description 5
- 230000036556 skin irritation Effects 0.000 description 5
- 231100000475 skin irritation Toxicity 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 125000005017 substituted alkenyl group Chemical group 0.000 description 5
- 125000000547 substituted alkyl group Chemical group 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 208000009621 actinic keratosis Diseases 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000002738 chelating agent Substances 0.000 description 4
- 229920001429 chelating resin Polymers 0.000 description 4
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 4
- 239000003642 reactive oxygen metabolite Substances 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 125000004426 substituted alkynyl group Chemical group 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- KUAZQDVKQLNFPE-UHFFFAOYSA-N thiram Chemical compound CN(C)C(=S)SSC(=S)N(C)C KUAZQDVKQLNFPE-UHFFFAOYSA-N 0.000 description 4
- 230000037317 transdermal delivery Effects 0.000 description 4
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010059313 Anogenital warts Diseases 0.000 description 3
- FCKYPQBAHLOOJQ-UHFFFAOYSA-N Cyclohexane-1,2-diaminetetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)C1CCCCC1N(CC(O)=O)CC(O)=O FCKYPQBAHLOOJQ-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- KGHNSNSWRMJVND-UHFFFAOYSA-N Hypocrellin Natural products COC1=CC(=O)C2=C3C4C(C(C(=O)C)C(C)(O)Cc5c(OC)c(O)c6C(=O)C=C(OC)C(=C13)c6c45)C(=C2O)OC KGHNSNSWRMJVND-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 206010051246 Photodermatosis Diseases 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 206010039580 Scar Diseases 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940089960 chloroacetate Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 210000004207 dermis Anatomy 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000005342 ion exchange Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 230000008845 photoaging Effects 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 210000000664 rectum Anatomy 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- QGKMIGUHVLGJBR-UHFFFAOYSA-M (4z)-1-(3-methylbutyl)-4-[[1-(3-methylbutyl)quinolin-1-ium-4-yl]methylidene]quinoline;iodide Chemical compound [I-].C12=CC=CC=C2N(CCC(C)C)C=CC1=CC1=CC=[N+](CCC(C)C)C2=CC=CC=C12 QGKMIGUHVLGJBR-UHFFFAOYSA-M 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- ILBBNQMSDGAAPF-UHFFFAOYSA-N 1-(6-hydroxy-6-methylcyclohexa-2,4-dien-1-yl)propan-1-one Chemical compound CCC(=O)C1C=CC=CC1(C)O ILBBNQMSDGAAPF-UHFFFAOYSA-N 0.000 description 2
- KHUFHLFHOQVFGB-UHFFFAOYSA-N 1-aminoanthracene-9,10-dione Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2N KHUFHLFHOQVFGB-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- BTQAFTBKHVLPEV-UHFFFAOYSA-N 3h-naphtho[2,3-e]indazole Chemical compound C1=CC=CC2=CC3=C4C=NNC4=CC=C3C=C21 BTQAFTBKHVLPEV-UHFFFAOYSA-N 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- RYQOILLJDKPETL-UHFFFAOYSA-N 5-aminolevulinic acid hexyl ester Chemical compound CCCCCCOC(=O)CCC(=O)CN RYQOILLJDKPETL-UHFFFAOYSA-N 0.000 description 2
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 208000013165 Bowen disease Diseases 0.000 description 2
- 208000019337 Bowen disease of the skin Diseases 0.000 description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 2
- JUDGRMABQJKRPW-XIADSQHASA-N CCC1=C(/C=C2\N=C(/C(\CC3=O)=C(/[C@@H](CCC(O)=O)[C@@H]4C)\N/C\4=C\C(C(C)=C4C=C)=N/C\4=C4)C3=C\2C)NC/4=C1C Chemical compound CCC1=C(/C=C2\N=C(/C(\CC3=O)=C(/[C@@H](CCC(O)=O)[C@@H]4C)\N/C\4=C\C(C(C)=C4C=C)=N/C\4=C4)C3=C\2C)NC/4=C1C JUDGRMABQJKRPW-XIADSQHASA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- 239000004909 Moisturizer Substances 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 206010033733 Papule Diseases 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 206010040830 Skin discomfort Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- RGHILYZRVFRRNK-UHFFFAOYSA-N anthracene-1,2-dione Chemical compound C1=CC=C2C=C(C(C(=O)C=C3)=O)C3=CC2=C1 RGHILYZRVFRRNK-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000003833 bile salt Substances 0.000 description 2
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 210000003679 cervix uteri Anatomy 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- SURLGNKAQXKNSP-DBLYXWCISA-N chlorin Chemical compound C\1=C/2\N/C(=C\C3=N/C(=C\C=4NC(/C=C\5/C=CC/1=N/5)=CC=4)/C=C3)/CC\2 SURLGNKAQXKNSP-DBLYXWCISA-N 0.000 description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 2
- 229930002875 chlorophyll Natural products 0.000 description 2
- 235000019804 chlorophyll Nutrition 0.000 description 2
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000003779 hair growth Effects 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- VANSZAOQCMTTPB-SETSBSEESA-N hypocrellin Chemical compound C1[C@@](C)(O)[C@@H](C(C)=O)C2=C(OC)C(O)=C3C(=O)C=C(OC)C4=C3C2=C2C3=C4C(OC)=CC(=O)C3=C(O)C(OC)=C21 VANSZAOQCMTTPB-SETSBSEESA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000005414 inactive ingredient Substances 0.000 description 2
- 229910052738 indium Inorganic materials 0.000 description 2
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical group [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 210000002510 keratinocyte Anatomy 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 150000002678 macrocyclic compounds Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- YUUAYBAIHCDHHD-UHFFFAOYSA-N methyl 5-aminolevulinate Chemical compound COC(=O)CCC(=O)CN YUUAYBAIHCDHHD-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000001333 moisturizer Effects 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- LKKPNUDVOYAOBB-UHFFFAOYSA-N naphthalocyanine Chemical compound N1C(N=C2C3=CC4=CC=CC=C4C=C3C(N=C3C4=CC5=CC=CC=C5C=C4C(=N4)N3)=N2)=C(C=C2C(C=CC=C2)=C2)C2=C1N=C1C2=CC3=CC=CC=C3C=C2C4=N1 LKKPNUDVOYAOBB-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229940042880 natural phospholipid Drugs 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 210000001732 sebaceous gland Anatomy 0.000 description 2
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- BQJKVFXDDMQLBE-UHFFFAOYSA-N shiraiachrome A Natural products COC1=C2C3=C(OC)C=C(O)C4=C3C3=C5C(CC(C)(O)C(C(C)=O)C3=C(OC)C4=O)=C(OC)C(=O)C(C(O)=C1)=C25 BQJKVFXDDMQLBE-UHFFFAOYSA-N 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 201000010153 skin papilloma Diseases 0.000 description 2
- 231100000245 skin permeability Toxicity 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 210000003708 urethra Anatomy 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 210000001215 vagina Anatomy 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- OWQPOVKKUWUEKE-UHFFFAOYSA-N 1,2,3-benzotriazine Chemical compound N1=NN=CC2=CC=CC=C21 OWQPOVKKUWUEKE-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical group C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 description 1
- YHIIJNLSGULWAA-UHFFFAOYSA-N 1,4-thiazinane 1-oxide Chemical group O=S1CCNCC1 YHIIJNLSGULWAA-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-OUBTZVSYSA-N 2,2,2-trichloroacetic acid Chemical class O[13C](=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-OUBTZVSYSA-N 0.000 description 1
- JXTHNDFMNIQAHM-OUBTZVSYSA-N 2,2-dichloroacetic acid Chemical class OC(=O)[13CH](Cl)Cl JXTHNDFMNIQAHM-OUBTZVSYSA-N 0.000 description 1
- HVUMOYIDDBPOLL-UHFFFAOYSA-N 2-(3,4-Dihydroxyoxolan-2-yl)-2-hydroxyethyl octadecanoate Polymers CCCCCCCCCCCCCCCCCC(=O)OCC(O)C1OCC(O)C1O HVUMOYIDDBPOLL-UHFFFAOYSA-N 0.000 description 1
- FCKYPQBAHLOOJQ-UWVGGRQHSA-N 2-[[(1s,2s)-2-[bis(carboxymethyl)amino]cyclohexyl]-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)[C@H]1CCCC[C@@H]1N(CC(O)=O)CC(O)=O FCKYPQBAHLOOJQ-UWVGGRQHSA-N 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical compound O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- MXCVHSXCXPHOLP-UHFFFAOYSA-N 4-oxo-6-propylchromene-2-carboxylic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=CC(CCC)=CC=C21 MXCVHSXCXPHOLP-UHFFFAOYSA-N 0.000 description 1
- 229950000258 5-aminolevulinic acid hexyl ester Drugs 0.000 description 1
- 206010000513 Acne pustular Diseases 0.000 description 1
- 206010056951 Actinic cheilitis Diseases 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- ZXBOZEUBGBNKPP-UHFFFAOYSA-N CC1=CC=C(COC(C(Cl)(Cl)Cl)=O)C=C1 Chemical compound CC1=CC=C(COC(C(Cl)(Cl)Cl)=O)C=C1 ZXBOZEUBGBNKPP-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010008263 Cervical dysplasia Diseases 0.000 description 1
- 206010008570 Chloasma Diseases 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000000907 Condylomata Acuminata Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 241000208680 Hamamelis mollis Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 208000000185 Localized scleroderma Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000003351 Melanosis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010027982 Morphoea Diseases 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000025610 Paget disease of the vulva Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 208000012641 Pigmentation disease Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 208000006787 Port-Wine Stain Diseases 0.000 description 1
- 208000006994 Precancerous Conditions Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 241001303601 Rosacea Species 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Polymers CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 1
- VGSOUDGIYSVAEU-UHFFFAOYSA-N acetic acid;2,2,2-trichloroacetic acid Chemical compound CC(O)=O.OC(=O)C(Cl)(Cl)Cl VGSOUDGIYSVAEU-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 230000002009 allergenic effect Effects 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 229940069521 aloe extract Drugs 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 210000002255 anal canal Anatomy 0.000 description 1
- 208000025009 anogenital human papillomavirus infection Diseases 0.000 description 1
- 201000004201 anogenital venereal wart Diseases 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000000058 anti acne agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940124340 antiacne agent Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004350 aryl cycloalkyl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QGKVXWDADKTZHW-UHFFFAOYSA-N azaporphyrin Chemical compound C1=C(N=2)C=CC=2C=C(N=2)C=CC=2C=C(N2)C=CC2=CC2=CNC1=N2 QGKVXWDADKTZHW-UHFFFAOYSA-N 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Chemical group 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 229940067596 butylparaben Drugs 0.000 description 1
- 229930188620 butyrolactone Natural products 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 208000007951 cervical intraepithelial neoplasia Diseases 0.000 description 1
- OEUUFNIKLCFNLN-LLVKDONJSA-N chembl432481 Chemical compound OC(=O)[C@@]1(C)CSC(C=2C(=CC(O)=CC=2)O)=N1 OEUUFNIKLCFNLN-LLVKDONJSA-N 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002910 effect on acne Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000005281 excited state Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 229910001448 ferrous ion Inorganic materials 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 125000005349 heteroarylcycloalkyl group Chemical group 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 150000002483 hydrogen compounds Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229940118199 levulan Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000000838 magnetophoresis Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 1
- 229940115057 methyl 5-aminolevulinate Drugs 0.000 description 1
- 125000006178 methyl benzyl group Chemical group 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940060184 oil ingredients Drugs 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940100460 peg-100 stearate Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- JZRYQZJSTWVBBD-UHFFFAOYSA-N pentaporphyrin i Chemical compound N1C(C=C2NC(=CC3=NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 JZRYQZJSTWVBBD-UHFFFAOYSA-N 0.000 description 1
- 231100000435 percutaneous penetration Toxicity 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 229940109328 photofrin Drugs 0.000 description 1
- 230000002165 photosensitisation Effects 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- RKCAIXNGYQCCAL-UHFFFAOYSA-N porphin Chemical compound N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 RKCAIXNGYQCCAL-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004308 pyranonyl group Chemical group O1C(C(=CC=C1)*)=O 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005494 pyridonyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000003716 rejuvenation Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000007964 self emulsifier Substances 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 230000036548 skin texture Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 201000011138 superficial basal cell carcinoma Diseases 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- SLGBZMMZGDRARJ-UHFFFAOYSA-N triphenylene Chemical compound C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C2=C1 SLGBZMMZGDRARJ-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 208000028010 vulval Paget disease Diseases 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 229940118846 witch hazel Drugs 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0061—5-aminolevulinic acid-based PDT: 5-ALA-PDT involving porphyrins or precursors of protoporphyrins generated in vivo from 5-ALA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/16—Halogenated acetic acids
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Birds (AREA)
- Gerontology & Geriatric Medicine (AREA)
- Toxicology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Cosmetics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
Abstract
本公開提供了5-胺基乙醯丙酸(5-ALA)的新鹽和5-ALA酯的新鹽,其製備,製劑,及作為光敏劑在光動力學治療,診斷和美容護理中的用途。
Description
本申請案主張2016年1月26日申請的美國臨時專利申請案第62/286,977號及2016年7月20日申請的中國專利申請案第201610568868.0號的優先權,以上申請案的全部內容以全文引用的方式並入本文中。
本公開涉及5-胺基乙醯丙酸(5-ALA)的鹽和5-ALA酯的鹽,其製備,製劑,及作為光敏劑在光動力學治療,診斷或在美容護理中的用途。
光動力學療法(PDT,又稱為光化療)是使用光敏劑和特定光源激發光敏劑的治療技術。在暴露於可見光的情況下,光敏劑被激發到高能態,並與氧反應或將能量轉移到氧分子以產生活性氧(ROS),例如單線態氧或氧自由基。ROS具有高細胞毒性,可導致惡性和異常細胞雕亡或壞死。激發態光敏劑也可部分回到低能量而產生紅色螢光,用於診斷。PDT在皮膚科治療,診斷和美容等領域有廣泛的臨床應用。
光動力學療法中最常用的光敏劑或前體是5-胺基乙醯丙酸(5-ALA)及其兩個酯,5-胺基乙醯丙酸甲酯(5-MAL)和5-胺基乙醯丙酸己酯(5-HAL)。人體大多數細胞可吸收並通過卟啉生物合成途徑轉化5-ALA或其酯為可光活化的卟啉,特別是高光敏活性的原卟啉IX(PpIX)。研究證實,癌細胞,癌前病變細胞或病變細胞傾向於比正常健康細胞積累更多的卟啉。這種選擇性積累是由異常細胞或組織的功能障礙所致,包括腫瘤中鐵螯合酶減少(Kemmner等,FASEB J,2008,22:500-509),或滲透性增強及滯留作用(Avci et al,J Biomed Nanottechnl,2014,10(9):1937-1952)。
5-ALA及其酯的PDT已證明是安全有效的治療某些癌症,癌前病症,非癌病症和癌症診斷的手段,有優異的美容效果(Fonda-Pascual等,Methods,2016,109,190-202;Jichlinski等,J Urol,2003,170:226-9)。由於這些治療劑不穩定並易聚合,故臨床上用的是其鹽酸鹽。美國批準了Levulan®(20% 5-ALA鹽酸鹽,DUSA Pharmaceuticals,Wilmington,MA,美國)治療光化性角化病。中國使用ALA(20%的5-ALA鹽酸鹽,復旦張江生物,上海)治療外部尖銳濕疣。Metvix®(16% 5-MAL鹽酸鹽,PhotoCure ASA,奧斯陸,挪威)用於治療光化性角化病,淺表基底細胞癌和Bowen氏病。高效光敏劑Hexvix®(5-HAL鹽酸鹽,PhotoCure ASA,奧斯陸,挪威)用於診斷膀胱癌。
5-ALA和5-MAL-PDT目前在多個臨床試驗和標簽外使用中治療中度至重度痤瘡(Mavilia等人,Br J Dematol,2007,157:779-846)。此外,臨床前和臨床研究表明,5-ALA及其酯PDT可有效治療細菌(Fotinos等人,Antimicrob Agents Chemother,2008,52:1366-1373)和真菌感染(Calzavara-Pinton等人,Photochem Photobiol,2012,88:512-522),炎症性疾病(如硬斑病,光化性唇炎,粉刺)和治療與病毒和癌症相關的感染(例如病毒性疣)。
Jeffry等人描述了5-ALA及其甲酯作為光動力美容治療劑(Arch Dermatol,2005,141:1247-1252)。Carrasco等人證實5-MAL-PDT引起的原位ROS能激活小鼠皮膚和毛囊乾細胞niche的細胞增殖,促進毛發生長,組織修復和傷口愈合(J Invest Dermatol,2015,135(11):2611-22)。本文所述的所有參考文獻通過引用並入本文。
然而,5-ALA及其酯的鹽酸鹽具有多種不良性質,包括刺激皮膚,炎症和光照時治療部位疼痛(Grapengiesser等人,Clin Exp Dermatol,2002,27:493-7),鹽酸鹽有吸濕性,藥物在儲存中降解和製劑中不穩定(Gadmar等人,J.Photochem。Photobiol B:Biol,2002,67:187-93)。外用5-ALA和5-MAL-PDT的另一個主要限制是光照射深度和藥物的皮膚滲透性不足。而滲透性不足被認為起主要作用。因此,提高皮膚滲透將會改進5-ALA及其酯PDT療效(Foster等人,Exp Dermatol,2010,19:806-12)。
US8,692,014描述了與鹽酸鹽相比,5-ALA
磺酸鹽的吸水性降低,細胞產生螢光強度提高。US8,173,839描述了5-ALA磷酸鹽比其鹽酸鹽對身體舌表面的刺激低。
三氯乙酸(TCA)是小分子有機酸,分子量大於乙酸和鹽酸。TCA是強化學腐蝕劑,廣泛作為外用藥和美容治療劑。三氯乙酸已被證明能夠滲透皮膚深層,凝結表皮蛋白質,破壞和去除損傷的皮膚細胞。TCA還具有抗菌和抗炎活性,並能刺激基底皮層細胞分裂形成新細胞,均勻分布自然的皮膚黑色素。TCA的療效通常依賴於其滲透深度,直接與其濃度成正比。低濃度TCA(10-20%)用於淺膚或表皮換膚術,TCA滲透並影響表皮和真皮-表皮的界面。該濃度範圍用於治療輕度光老化,黃褐斑,粉刺性痤瘡和炎症後紅斑。20-50% TCA用於中等深度或真皮換膚術,TCA通過表皮滲透到乳頭狀真皮,用於治療中度光老化,光化性角化病和輕度痤瘡疤痕(Di等人,Photodermatol Photoimmunol Photomed 2015,233-8)。50%或更高濃度的TCA用於深層換膚術,TCA可滲透到中真皮網狀層,用於治療外部生殖器疣和痤瘡疤痕(Yanofsky等,Expert Rev Dermatol,2013,8:321-332;Agarwal等,Dermatol Surg,2015,41:597-604)。
TCA換膚術和5-ALA或5-MAL PDT都廣泛用於治療皮膚病和美容,但通常顯示出不同的治療特征。例如,在治療尋常痤瘡時,TCA換膚術適於治療粉刺性痤瘡/非炎症,而對丘疹痤瘡/炎症性顯示中度改善(Meguid
等,Dermatol Surg,2015,41:1398-1404)。相比之下,5-ALA PDT對丘疹膿皰型痤瘡(炎症性)的療效顯著,而對粉刺性痤瘡(非炎症性)的治療效果不佳。不同的療效可從兩種療法的不同機制得到解釋。5-ALA PDT選擇性地破壞皮脂腺(Wan等,Clin,Cosm Invest Dermatol,2014,7:145-163)。而TCA治療痤瘡的機制被認為是由於減少角質細胞的凝聚和角化細胞堵塞。因此,如果使用5-ALA或其酯和TCA形成的鹽,可以提供協同效應或雙重活性治療痤瘡及本文所述的其它疾病或病症。同時,本發明人發現與相對應鹽酸鹽相比,5-ALA或其酯和TCA所成鹽對身體敏感表面(如舌表面)刺激性降低。本發明人還發現,5-MAL和5-HAL的TCA鹽具有抗濕性,比相對應的鹽酸鹽的吸濕性低得多。
在第一方面,新鹽的結構如通式(I)所示:H2NCH2COCH2CH2COOR‧X-COOH (I)
R和X定義如下。
在第二方面,製備5-ALA或其衍生物的鹽的方法包括:提供N-保護基-5-胺基乙醯丙酸或衍生物的溶液;加入氫化催化劑,H2和X-COOH以得到5-ALA或其衍生物的鹽。X定義如下。
在第三方面,製備5-胺基乙醯丙酸鹽或其衍生物的方法包括:使5-胺基乙醯丙酸或其衍生物通過樹
脂;收集洗脫液;並將洗脫液與X-COOH混合,得到5-胺基乙醯丙酸或其衍生物的鹽。X定義如下。
本公開涉及5-胺基乙醯丙酸(5-ALA)及其酯的鹽,特別是三氯乙酸鹽。如本公開所述,選擇與5-ALA及其酯形成新鹽的酸可以在PDT中提供協同治療作用或雙重活性。此外,本公開的新鹽具有改進的物化性質,例如吸水性降低,而吸水性是製備和儲存中質量控制的重要因素,及對皮膚的刺激性比相對應的鹽酸鹽低。
當描述本公開的化合物,鹽,組合物,方法和工藝流程時,除非另有說明,以下是所述術語的含義。
術語“鹵原子”或“鹵素”是指氯,溴,碘或氟原子。
術語“烷基”是指-具有指定碳原子數(即,C2-12表示2至12個碳原子)的直鏈,環狀或支鏈或其組合的烴基。烷基的實例包括甲基,乙基,正丙基,異丙基,正丁基,叔丁基,異丁基,仲丁基,環己基,環戊基,(環己基)甲基,環丙基甲基,雙環[2.2.1]庚烷,雙環[2.2.2]辛烷等。除非另有說明,烷基可以是取代或未取代的。取代的烷基的實例包括鹵代烷基,硫代烷基,胺基烷基等。
術語“烯基”是指含有至少一個碳-碳雙鍵的烴基。烯基可包括例如烯丙基,1-丁烯基,2-己烯基和3-辛烯基。除非另有說明,烯基可以是取代或未取代的。
術語“炔基”是指含有至少一個碳-碳三鍵的烴基。炔基可以包括例如乙炔基,炔丙基和3-己炔基。除非另有說明,炔基可以是取代或未取代的。
術語“芳基”是指有多個不飽和鍵的芳烴基團,有5-10個原子並形成單環(單環,優選具有6個原子如苯基)或多個環(雙環(優選具有10個原子如萘基)或多環),其可以被共同融合或共價連接。芳基的實例包括苯基和萘-1-基,萘-2-基,聯苯基等。芳基可以是取代或未取代的,除非另有說明。
術語“雜芳基”是指含有5-10個原子和至少一個雜原子(例如S,N,O,Si)的芳族基團,其中雜芳基可以是單環的(優選5或6個原子)或雙環(優選9或10個原子)。例子包括吡啶基,噠嗪基,吡嗪基,嘧啶基,三嗪基,喹啉基,喹喔啉基,喹唑啉基,噌啉基,酞嗪基,苯並三嗪,嘌呤基,苯並咪唑基、苯並吡唑類、苯並三唑基,苯並異噁唑基,異苯並呋喃基,異吲哚基,吲哚嗪基,苯並三嗪基,噻吩並吡啶基,噻吩並嘧啶基,吡唑並嘧啶基,咪唑並吡啶基,苯並噻吩基,苯並呋喃基,苯並噻唑基,吲哚,喹啉,異喹啉,異噻唑,吡唑基,吲唑基,蝶啶基,咪唑基,三唑,四唑基,噁唑基基,異噁唑,噁二唑基,噻二唑基,吡咯基,噻吩基,呋喃基或噻唑基。
術語“環烷基”是指飽和單環,雙環,三環或其它多環烴基。任何原子都可以被一個或多個取代基取代。環碳用作環烷基與另一部分的連接點。環烷基可以
含有稠環。熔融環是共享同碳原子的環。環烷基可以包括例如環丙基,環丁基,環戊基,環己基,環庚基,金剛烷基和降冰片基(雙環[2.2.1]庚基)。
本文所用術語“雜環基”或“雜環”是指含有至少5-10個原子(優選5或6個)和至少一個雜原子(通常為1個至5個)的飽和或不飽和非芳族環,雜原子選自氮,氧或硫。雜環基可以是單環(優選5或6個原子)或雙環(優選9或10個原子)。如果是單環,則環系統具有1-4個雜原子,如果是雙環,則具有1-8個雜原子,如果是三環,則具有1-10個雜原子,選自O,N或S雜原子(以及它們的單和二氧化物,例如N→O-,S(O),SO2)。雜環基可以含有稠環。熔融環是共享同碳原子的環。雜環基的實例包括吡咯烷基,哌啶基,咪唑烷基,吡唑烷基,丁內醯胺基,戊內醯胺基,咪唑啉酮基,乙內醯脲基,二氧戊環基,鄰苯二甲醯亞胺基,1,4-二噁烷基,嗎啉基,硫代嗎啉基,硫代嗎啉-S-氧化物基,硫代嗎啉-S,S-二氧化物基,哌嗪基,吡喃基,吡啶酮基,3-吡咯啉基,噻喃基,吡喃酮基,四氫呋喃基,四氫噻吩基,奎寧環基等。
術語“環”指原子以環狀排列的化合物,可以是碳環或雜環。
術語“取代基”指取代基團,例如烷基,環烷基,烯基,炔基,芳烷基,雜芳烷基,雜環基,雜鏈烯基,環烯基,芳基,雜芳基,芳基環烷基,雜芳基環烷基,芳基環烯基,雜芳基環烯基,芳基雜環基,雜芳基雜
環基,芳基雜環烯基或雜芳基雜環烯基。在一個方面,基團上的取代基是獨立地任何單一,兩種或更多種允許的原子或基團的任何組合,另一方面,取代基本身可以被上述任何一個取代基所取代。
通常,除非另有說明,取代基(基團)前綴名稱是從母體氫化物衍生的,方法(i)母體氫化物中的“ane”用後綴“yl”,“diyl”,“triyl”,“tetrayl”等代替;或者(ii)母體氫化物中的“e”用後綴“yl”,“diyl”,“triyl”,“tetrayl”等代替(給自由價原子盡量低的與母體氫物的任何已建立的編號相一致的數字)。可接受的簡稱,例如金剛烷基,萘基,蒽基,菲基,呋喃基,吡啶基,異喹啉基,喹啉基和哌啶基,常規的名稱,例如乙烯基,烯丙基,苯基和噻吩基在此是通用的。常規編號/字母系統也適於稠合,雙環,三環,多環的取代基編號和命名。
通常,當特定可變的定義包括氫和非氫(鹵素,烷基,芳基等)的可能性時,術語“除氫之外的取代基”統稱該特定可變的為非氫的可能性。
在一些實施方案中,所有上述術語(例如,“烷基”,“芳基”,“雜芳基”等)包括所指基團的取代和未取代的形式。這些基團可以有化學上允許的多取代。
本文所用的術語“組合物”旨在包括含有特定量的特定成分的產品,以及直接或間接由特定量的特定成分的組合產生的任何產品。“藥學上可接受的”是指載體,稀釋劑或賦形劑必須與製劑的其它成分相容,對其
接受者無害。
本發明的鹽的藥物組合物可以方便地以單位劑量形式存在,並可通過藥學領域熟知的任何方法製備。所有方法包括使活性成分與一種或多種構成輔助成分的載體結合的步驟。通常,藥物組合物通過均勻且完全地將活性成分與液體載體或細碎固體載體或兩者混合。如果需要,然後將產物製備成所需製劑。在藥物組合物中,活性化合物的含量足以對疾病或病症產生治療效果。
含有活性成分的藥物組合物可適於口服,例如片劑,錠劑,含片,水性或油性懸浮液,可以是分散的粉末或顆粒劑,乳液和自乳化劑,硬或軟膠囊,糖漿或酏劑。用於口服的組合物可根據本領域已知的任何方法製備。組合物可以含有一種或多種選自甜味劑,調味劑,著色劑和防腐劑的試劑,以提供藥學上宜人可口的製劑。片劑含有活性成分與適用於製造片劑的其它無毒的藥學上可接受的賦形劑混合。這些賦形劑可以是例如惰性稀釋劑如纖維素,二氧化矽,氧化鋁,碳酸鈣,碳酸鈉,葡萄糖,甘露醇,山梨醇,乳糖,磷酸鈣或磷酸鈉;造粒和崩解劑,例如玉米澱粉或海藻酸;黏合劑,例如PVP,纖維素,PEG,澱粉,明膠或阿拉伯樹膠,以及潤滑劑,例如硬脂酸鎂,硬脂酸或滑石。片劑可以是未包衣的,或可以通過已知技術以腸道或其他方式包衣以延遲在胃腸道中的崩解和吸收,從而提供在較長時間內的持續的作用。例如,可以使用延時材料,例如單硬脂酸甘油酯或二硬脂酸甘油酯。
用於口服的製劑也可以呈現為硬明膠膠囊,其中活性成分與惰性固體稀釋劑例如碳酸鈣,磷酸鈣或高嶺土混合,或作為軟明膠膠囊,其中活性成分與水或油介質混合,例如花生油,液體石蠟或橄欖油。
另外,乳劑可以用非水混溶性成分如油製備,並用表面活性劑例如單甘油二酯,PEG酯等來穩定。
水性懸浮液含有活性物質與適於製備水性懸浮液的賦形劑。這種賦形劑是懸浮劑,例如羧甲基纖維素鈉,甲基纖維素,羥丙基甲基纖維素,藻酸鈉,聚乙烯吡咯烷酮,黃蓍膠和阿拉伯膠;分散劑或潤濕劑可以是天然磷脂,如卵磷脂,或氧化烯與脂肪酸的縮合物,例如聚氧乙烯硬脂酸酯,或環氧乙烷與長鏈脂族醇的縮合物,例如十七烷基乙氧基鯨蠟醇,或環氧乙烷與衍生自脂肪酸的偏酯的縮合物,以及己糖醇如聚氧乙烯山梨糖醇單油酸酯,或環氧乙烷與衍生自脂肪酸和己糖醇酐的偏酯的縮合物,例如聚乙烯脫水山梨糖醇單油酸酯。水性懸浮液還可以含有一種或多種防腐劑,例如乙基或正丙基對羥基苯甲酸酯,一種或多種著色劑,一種或多種調味劑和一種或多種甜味劑,例如蔗糖或糖精。
適於通過添加水製備水性懸浮液的可分散粉末和顆粒使活性成分與分散劑或潤濕劑,懸浮劑和一種或多種防腐劑相混合。合適的分散劑或潤濕劑和懸浮劑的實例是上面已經提到的。還可以是另外的賦形劑,例如甜味劑,調味劑和著色劑。
本公開的藥物組合物還可以是水包油乳液。油相可以是植物油,例如橄欖油或花生油,或礦物油,例如液體石蠟或它們的混合物。合適的乳化劑可以是天然的樹膠,例如阿拉伯樹膠或黃蓍膠,天然的磷脂,例如大豆,卵磷脂和衍生自脂肪酸和己糖醇酐的酯或偏酯,例如脫水山梨醇單油酸酯和所述的偏酯與環氧乙烷縮合物,例如聚氧乙烯山梨糖醇酐單油酸酯。乳液還可以含有甜味劑和調味劑。本公開的鹽也可是直腸給藥的栓劑。這些組合物可以通過將藥物與適當的無刺激性賦形劑混合來製備,所述賦形劑在常溫下為固體但在直腸溫度下為液體,在直腸中熔化釋放藥物。這些材料是可可脂和聚乙二醇。此外,本公開的鹽可以通過溶液或軟膏施用眼腈遞送。此外,目標鹽的透皮遞送可以通過離子電滲貼片等實現。
對於外用,使用含有本公開的鹽的霜劑,軟膏,凝膠劑,溶液或懸浮液。外用也包括漱口劑和含漱劑。
本公開的藥物組合物和方法還可包含本文所述的其它有治療活性的化合物,例如用於治療上述病理狀況的那些化合物。
“藥學上可接受的”載體,稀釋劑或賦形劑是指與製劑的其它成分相容的載體,稀釋劑或賦形劑,對其接受者無害。
“藥學上有效量”是指給予需要治療的患者時足以實現治療的量。
本文所用“治療”是指治療患者的疾病或醫學病症(例如癌症),例如哺乳動物(特別指人或伴侶動物),包括:改善疾病或醫學病症,即消除或引起患者的疾病或醫學病症的消退;抑制疾病或醫學病症,即減緩或阻止患者的疾病或醫學病症的發展;減輕患者的疾病或醫學病症的症狀。
本公開的某些鹽可以非溶劑化以及溶劑化形式存在,包括水合形式。通常,溶劑化形式和非溶劑化形式均包括在本發明的範圍內。
本公開的某些鹽可以多種結晶或無定形形式存在(即多晶型物)。通常,所有物理形式是和本公開所預期的用途相一致的,均包括在本發明的範圍內。
本公開的鹽可以在一個或多個原子處含有非天然比例的原子同位素。例如,鹽可以用放射性同位素標記,例如氚(3H),碘-125(125I)或碳-14(14C)。本發明鹽的所有同位素變化,無論是否是放射性的,均包括在本發明的範圍內。
通式(I)的鹽可以單獨施用或與一種或多種其它治療劑組合施用,采用固定組合施用、交錯或彼此獨立形式施用一種本發明化合物和一種或多種其它治療劑。
本公開提供了具有通式(I)的鹽:
H2NCH2COCH2CH2COOR‧X-COOH (I)。
R選自氫,未取代或取代的烷基,未取代或取代的烯基,未取代或取代的炔基,未取代或取代的碳環,未取代或取代的C6-12芳基,未取代或取代的3-12元雜環,和未取代或取代的5-12元雜芳基。
X選自氫,-CY1R1R2,-CY1Y2R1和-CY1Y2Y3。Y1,Y2和Y3獨立地選自F,Cl,Br和I。R1和R2獨立地選自氫,未取代或取代的烷基,未取代或取代的烯基,未取代或取代的炔基,未取代或取代的碳環,未取代或取代的C6-12芳基,未取代或取代的3-12元雜環,以及未取代或取代的5-12元雜芳基。R1和R2可以與其所連接的一個原子或多個原子結合形成未取代或取代的C3-12環烷基,未取代或取代的3-至12-元雜環,未取代或取代的C6-12芳基,或未取代或取代的5-至12元雜芳基。
在一些實施方案中,R是氫。
在一些實施方案中,R是取代或未取代的C1-20烷基。在一些實施方案中,R是未取代的C1-8烷基。在一些實施方案中,R選自甲基,乙基,丙基,丁基,戊基,己基,仲丙基,仲丁基,叔丁基,仲戊基和仲己基。在一些實施方案中,R是甲基。在一些實施方案中,R是己基。在一些實施方案中,R為芐基。在一些實施方案中,R是甲基芐基。
在一些實施方案中,R是被選自羥基,硫醇,羧基,胺基甲醯基,酯,胺基,烷基-胺基,醯胺,鹵
素,硝基和氰基中的至少一種取代的烷基。
在一些實施方案中,R是未取代或取代的碳環。在一些實施方案中,R是未取代的或取代的C3-6碳環。在一些實施方案中,R選自環丙基,環丁基,環戊基和環己基。
在一些實施方案中,R是未取代的或取代的C6-12芳基。在一些實施方案中,R是未取代的或取代的芐基。在一些實施方案中,R選自芐基,2-甲基芐基,4-甲基芐基,2-氯-芐基,4-氯-芐基,2-硝基-芐基,4-硝基-芐基,2-異丙基芐基,4-異丙基芐基,2-氟-芐基和4-氟-芐基。
在一些實施方案中,R選自氫,甲基,乙基,丙基,丁基,戊基,己基,仲丙基,仲丁基,叔丁基,仲戊基,仲己基,環丙基,環丁基,環戊基,環己基,芐基,2-甲基芐基,4-甲基芐基,2-氯-芐基,4-氯-芐基,2-硝基-芐基,4-硝基-芐基,2-異丙基芐基,4-異丙基芐基,2-氟-芐基和4-氟-芐基。
在一些實施方案中,X是-CY1H2。Y1是Cl或F。在一些實施方案中,Y1是Cl。在一些實施方案中,X是-CY1Y2H。Y1和Y2獨立地選自Cl和F.在一些實施方案中,Y1和Y2是Cl。在一些實施方案中,X是-CY1Y2Y3。Y1,Y2和Y3獨立地選自Cl和F.在一些實施方案中,Y1,Y2和Y3是Cl。
在一些實施方案中,X選自-CH2Cl,-CHCl2和-CCl3。在一些實施方案中,X是-CCl3。在一些實施方案
中,X是-CH2Cl。
在一些實施方案中,X-COOH選自2-氯乙酸和2,2,2-三氯乙酸。
在一些實施方案中,所述鹽選自5-胺基乙醯丙酸2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸甲酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸己酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸2或4-甲基芐酯2,2,2-三氯乙酸鹽。
優選的鹽包括2-胺基乙醯丙酸2-單氯乙酸鹽,5-胺基乙醯丙酸2.2-二氯乙酸鹽,5-胺基乙醯丙酸2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸甲酯2-單氯乙酸甲鹽,5-胺基乙醯丙酸甲酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸甲酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸乙酯2-單氯乙酸鹽,5-胺基乙醯丙酸乙酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸乙酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸丙酯2-氯乙酸鹽,5-胺基乙醯丙酸丙酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸丙酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸丁酯2-單氯乙酸鹽,5-胺基乙醯丙酸丁酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸丁酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸戊酯2-氯乙酸鹽,5-胺基乙醯丙酸戊酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸戊酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸己酯2-氯乙酸鹽,5-胺基乙醯丙酸己酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸己酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸芐酯2-氯乙酸鹽,5-胺基乙醯丙酸芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸芐酯
2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸2-甲基芐酯2-氯乙酸鹽,5-胺基乙醯丙酸2-甲基芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸2-甲基芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸4-甲基芐酯2-氯乙酸鹽,5-胺基乙醯丙酸4-甲基芐基酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸4-甲基芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸4-氯芐酯2-氯乙酸鹽,5-胺基乙醯丙酸4-氯芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸4-氯芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸4-硝基芐酯2-氯乙酸鹽,5-胺基乙醯丙酸4-硝基芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸4-硝基芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸4-異丙基芐酯2-氯乙酸鹽,5-胺基乙醯丙酸4-異丙基芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸4-異丙基芐酯2,2,2-三氯乙酸鹽。並且美國專利公開2015/0191419中描述的5-ALA的酯類似物能與本公開中描述的有機酸反應形成新的鹽(特別是三氯乙酸),其全部內容通過引用並入本文。
本公開的新鹽能被細胞攝取並轉化成具有光敏活性的內源性卟啉,表明新鹽是有效用的PDT治療劑。這些新鹽可以作為原料,或優選作為藥物組合物使用。因此,根據另一方面,本公開提供了藥物組合物,包含本公開的鹽化合物和至少一種藥學或化妝品可接受的賦形劑或載體以及可任選一種或多種治療成分。
在一些實施方案中,組合物包含通式(I)的鹽和至少一種藥學上或美容上可接受的載體。在一些實施
方案中,組合物還包含羥基乙基纖維素凝膠。在一些實施方案中,組合物包含通式(I)的鹽,鹽含量約0.01%至約95%(重量)。在一些實施方案中,鹽的含量約0.1%至約50%。在一些實施方案中,鹽為約0.1%至約20%(重量)。
在一些實施方案中,組合物包含通式(I)的鹽和羥基乙基纖維素凝膠。在一些實施方案中,羥基乙基纖維素凝膠具有約250k至約725k的分子量。在一些實施方案中,組合物包含通式(I)的鹽,其鹽為約0.01%至約95%(重量)。在一些實施方案中,鹽的重量約0.1%至約50%。在一些實施方案中,鹽為約0.1%至約20%(重量)。
在一些實施方案中,組合物包含通式(I)的鹽和乳霜,例如Unguentum Merck霜(Almirall Hermal)或Cetaphil@(Galderma)。在一些實施方案中,組合物包含通式(I)的鹽,其鹽為約0.01%至約99%(重量)。在一些實施方案中,鹽的重量為約0.1%至約50%。在一些實施方案中,鹽為約0.1%至約20%(重量)。
在一些實施方案中,組合物包含作為第一光敏劑的通式(I)的鹽和第二光敏劑。第二光敏劑可以是任何合適的試劑。例如,第二光敏劑選自銦結合的焦脫鎂葉綠酸,衍生自吡咯的大環化合物,卟啉,二氫卟酚,酞菁,氯化銦甲基焦脫鎂葉綠素,萘酞菁,卟吩,卟啉菁,五烯吡酮,卟啉,苯並菲林,葉綠素,氮雜卟啉,紫杉酚,蒽二酮,蒽吡唑,胺基蒽醌,吩噁嗪染料,光敏素,竹紅菌素及其衍生物。
本公開的鹽可以任何常規形式與一種或多種適用於皮膚,身體內部表面,口腔,直腸內和系統給藥的藥學或化妝品可接受的載體或賦形劑配製,通過使用公知的技術。本文提及的賦形劑均可商購並出版在文獻中(例如,Hoepfner等,Fiedler Encyclopedia of Excipients for Pharmaceuticals,Cosmetics and Related Areas,Edition Cantor,Munich,2002)。外用製劑或組合物是優選的,例如粉末,溶液,凝膠,霜劑,軟膏劑,噴霧劑,洗劑,棒劑,陰道栓劑或噴霧劑。本文所述組合物中的賦形劑或載體包括水基或油基,增稠劑或膠凝劑,水凝膠,乳化劑,納米乳化劑,分散劑,增溶劑,穩定劑,懸浮劑和分散劑,著色劑或推進劑。製備本文所述製劑的技術是本領域已知的,本領域技術人員將能夠選擇本發明藥物或化妝品組合物所需的適當賦形劑。
對於口服,腸胃外給藥或皮內(例如皮下,腹膜或靜脈),組合物可以配製成片劑,膠囊,懸浮液和含有本公開的活性成分的溶液和一種或多種載體和/或稀釋劑,包括水,乙醇,甘油,山梨糖醇,玉米澱粉,乳糖,蔗糖,微晶纖維素,硬脂酸鎂,聚乙烯吡咯烷酮,檸檬酸,酒石酸,丙二醇,硬脂醇,丙二醇,硬脂醇,聚乙二醇,羧甲基纖維素或脂肪物質,鹽水和緩衝溶液。
外用製劑可以采取各種劑型中的任一種,包括溶液,懸浮液,軟膏和固體插入物,水凝膠栓劑。實
例是霜劑,洗劑,凝膠劑,軟膏劑,栓劑,噴霧劑,泡沫劑,搽劑,氣溶膠劑,口腔和舌下片劑,用於通過皮膚和黏膜吸收的各種被動和活性局部裝置,包括透皮應用等。
外用製劑的典型的藥學上可接受的載體是例如水,水和水混溶性溶劑如低級鏈烷醇或植物油的混合物,以及水溶性藥學上可接受的無毒聚合物,例如藻酸鹽,纖維素衍生物如甲基纖維素。本文所述的方法和組合物可以使用局部應用的典型的乳劑或軟膏型載體包括水,甘油,丙二醇和對羥基苯甲酸甲酯的混合物。局部載體還可以包括其它常規乳化劑和軟化劑,包括藻酸鹽,硬脂酸甘油酯,硬脂酸PEG-100,鯨蠟醇,對羥基苯甲酸丙酯,對羥基苯甲酸丁酯,山梨糖醇,聚乙氧基化脫水山梨糖醇單硬脂酸酯(TWEEN),白凡士林(VASELINE),三乙醇胺,Em油,蘆薈提取物,羊毛脂,可可脂等。合適的局部載體是本領域技術人員熟知的。
例如,將Unguentum Merck(Almirall Hermal)或Cetaphil@(Galderma)混合在所述的組合物中。通常,Unguentum Merck基質或Cetaphil@將占組合物總量的約70%,更優選的約占80%。可替代的軟膏基質是本領域技術人員已知的,例如Lipoderm@(PCCA)。
在一些實施方案中,製劑包含式(I)的鹽和乳霜,例如Unguentum Merck霜(Almirall Hermal)或Cetaphil@(Almirall Hermal)。在一些實施方案中,製劑包含式(I)的鹽,其鹽為約0.01%至約99%(重量)。在一些實施
方案中,鹽的重量為約0.1%至約50%。在一些實施方案中,鹽為約0.1%至約20%(重量)。
典型的透皮製劑包含常規水性或非水性載體,例如霜劑,軟膏劑或糊劑,或是藥膏,貼片或膜的形式。
如本文所用,透皮遞送還包括本領域已知的活性劑透皮遞送的許多不同系統。透皮遞送系統包括但不限於被動裝置,例如藥物黏性透皮貼劑和“活性”透皮技術,例如離子電滲法,電穿孔法,超聲波滲透法,磁電泳法,微針裝置,無針注射法和使用熱能使皮膚更易滲透。
本公開的鹽和組合物可以與其它光敏劑(例如Photofrin,hypocrellins等)配製或施用以增強治療功效。還可以使用其它藥劑來增加PpIX的積累和吸收,包括文獻中公開的任何螯合劑(如EDTA,CDTA等)螯合阻斷PpIX轉化為血紅素的亞鐵離子;並且文獻中描述的任何表面滲透助劑(例如DMSO,表面活性劑或非表面活性劑,脂肪酸和膽汁鹽)可用於增強本公開的鹽的吸收。
表面滲透劑可在約0.2至約50%(重量/體積)範圍使用,例如,約5%。
螯合劑可在約0.05至約20%(重量/體積)使用,例如,約0.1至約5%。
本文所述的組合物還可以包含通常在外用製劑中混合的非生理活性成分或組分。例如,組合物還可以包括其它成分,例如其他載體,保濕劑,油,脂肪,蠟,
表面活性劑,增稠劑,抗氧化劑,黏度穩定劑,螯合劑,緩衝劑,防腐劑,香料,染料,低級鏈烷醇,保濕劑,潤膚劑,分散劑,抗菌劑,抗真菌劑,消毒劑,維生素,抗生素或其它抗痤瘡劑,以及對局部組合物的活性沒有顯著不良影響的其它合適的材料。包含在載體中的另外的非活性成分可以是酸式磷酸鹽保濕劑,金縷梅提取物載體,甘油保濕劑,杏仁油潤滑劑,玉米油分散劑等,這些在下面進一步詳述。本領域技術人員將容易地認識到可以在本文所述的組合物中混合另外的非活性成分。
用於光動力學治療或診斷的試劑盒包括含有藥學上或美容上有效量的式(I)的鹽或其組合物的第一容器和包含溶解介質的第二容器。第二容器還可以包含載體,螯合劑,包括EDTA,CDTA和表面滲透劑如DMSO,表面活性劑或非表面活性劑,脂肪酸或膽汁鹽中的至少一種。
在一些實施方案中可以包括表面滲透劑,以優化式(I)的鹽通過角質層並進入真皮/皮膚瘤的局部作用。關於在外用製劑中使用滲透增強劑的討論,通常參見Percutaneous Penetration Enhancers(Eric W.Swith & Howard I.Maibach eds.1995):Ghosh等17 Pharm Tech,72(1993);Ghosh等17 Pharm Tech,62(1993);Ghosh等17 Pharm Tech,68(1993),所有這些在此通過引用並入本文。滲透劑應該是藥理惰性的,無毒的和非過敏的,具有快速和可逆的作
用,並且與本發明的組合物相容。
滲透劑的實例包括但不限於乙醇,異丙醇,月桂醇,水楊酸,八聚苯基聚乙二醇,聚乙二醇400,丙二醇,N-癸基甲基亞碸,DMSO和氮雜環化合物,如US4,755,535;US4,801,586;US4,808,414和US4,920,101所述,這些專利通過引用並入本文。
在一個實施方案中,溶解介質是水性或非水性介質。在一個實施方案中,溶解介質是氯化鈉溶液。在一些實施方案中,水溶液為約0.9%氯化鈉溶液。在一些實施方案中,水溶液是緩衝溶液。在一些實施方案中,水溶液是磷酸鹽緩衝鹽水。
在一些實施方案中,式(I)的鹽是第一光敏劑,第二容器包含第二光敏劑。第二光敏劑可以是任何合適的試劑。在一些實施方案中,第二光敏劑選自銦結合的焦脫鎂葉綠酸,衍生自吡咯的大環化合物,卟啉,二氫卟酚,酞菁,氯化銦甲基焦脫鎂葉綠素,萘酞菁,卟吩,卟啉菁,五烯吡酮,卟啉,苯並二氫葉酸,葉綠素,吖庚因,紫嘌呤,蒽二酮,蒽吡唑,胺基蒽醌,吩噁嗪染料,光敏素,竹紅菌素及其衍生物。
一方面,本公開提供了在治療部位通過細胞外施用式(I)的新鹽或組合物,由卟啉生物合成途徑在細胞內產生光敏劑卟啉(特別是PpIX)的方法。隨後用光活化治療部位的卟啉引起細胞毒。因此,本公開的鹽及其藥物
組合物可用於PDT治療身體內外表面的疾病或病症。
本文所述的身體的內表面和外表面包括皮膚,所有上皮和黏膜表面,例如皮膚和結膜,鼻通道,鼻竇,氣管,支氣管,口腔,咽,食道,胃,腸,直腸和肛管;輸尿管,膀胱和尿道的內壁;陰道,子宮頸和子宮內壁。
在另一方面,本公開的新鹽具有許多優點優於目前臨床使用的相對應鹽酸鹽。本公開的鹽比5-ALA或其酯的鹽酸鹽吸濕性低,由此可以降低因含水量高引起的不穩定性和分解,有利於生產中質量控制的一致性。本公開的鹽對皮膚刺激性比其相對應的鹽酸鹽小。當對尿道,直腸,陰道和子宮頸等敏感表面進行治療時,特別是需要多次治療時,皮膚刺激性降低是理想的。在細胞產生螢光的測量中,本公開的鹽的活性與相應的鹽酸鹽的活性相似。此外,本公開的新鹽中的酸如TCA可以提供雙重活性和/或增強5-ALA或其酯在PDT中的皮膚滲透性。
在一些實施方案中,用於治療受試者靶組織的光動力療法包括:向治療部位施用有效量的式(I)的鹽或組合物;孵育一段時間使式(I)的鹽或組合物得到足夠的吸收和轉化為PpIX;將治療部位暴露於一定波長和量的光照下從而有效地誘導細胞毒性;達到對受試者的靶組織進行光動力學治療。
在一些實施方案中,光的波長為約400至約1000nm。在一些實施例中,波長為約380至約440nm。在
一些實施方案中,波長為約620至約750nm。
在一些實施方案中,靶組織是皮膚,並且該方法用於治療皮膚病。
在一些實施方案中,靶組織是皮膚,該方法用於皮膚狀況的美容處理。皮膚狀況包括彌漫性或斑駁性色素沈著,紅斑痤瘡,皮脂腺增生,光老化,太陽損傷的皮膚粗糙,皺紋,毛孔和皮膚紋理增加,痤瘡,痤瘡疤痕,觸覺粗糙,黯淡和暗沈的皮膚。
在一些實施方案中,該方法用於皮膚年輕化。
在一些實施方案中,該方法用於治療癌症,基底細胞癌,宮頸上皮內瘤變,光化性角化病,Bowen氏病,外陰Paget氏病,痤瘡,尋常型痤瘡,牛皮癬,鮮紅斑痣,紅斑狼瘡,尖銳濕疣,難治性掌跖疣,皮膚T細胞淋巴瘤,細菌感染,真菌感染,炎症疾病和病毒感染。
在一些實施方案中,該方法用於促進毛發生長,組織修復和傷口愈合。
在一些實施方案中,癌症包括膀胱癌,結腸直腸癌,肺癌,腦癌,胃癌,子宮癌,皮膚癌和口腔癌,直腸癌和膽管癌。
式(I)或其組合物的施用可通過口服途徑,器官滴註,註射,無針註射或局部/外用途徑。
光源可以是燈(例如螢光燈),激光,發光二極管(LED)或過濾的強脈沖光。可以使用光纖到達不可接近
的部位。光波長可以在約300至約1200nm的範圍內,優選在約380至約800nm的範圍內。光照的劑量水平為約5至約200J/cm2,優選為約10至約120J/cm2。日光也可用作替代光源(Rubel等人,Br J Dermatol,2014,171,1164-1171)。施用藥物和光照之間的間隔(孵育時間)可以是約0.1至約24小時,優選約0.3至約4小時。對於PDD,首先使用紅光(例如600-750nm)檢查目標區域,然後用藍光檢查(例如380-440nm)以評估螢光水平。
組合物中鹽的濃度可以為約0.01至約95%(w/w或w/v),優選約0.1至約50%(w/w),約0.1至約30%,或約0.1至約20%。有效劑量可以根據諸如年齡,體重,病變面積和疾病狀況,或不同目的(如化妝品,治療或診斷)等因素來確定。通常,有效劑量在約0.001至約3g/天的範圍內,優選在約0.01至約2g/天的範圍內。
用於治療的示例性鹽是5-胺基乙醯丙酸2-單氯乙酸鹽,5-胺基乙醯丙酸2.2-二氯乙酸鹽,5-胺基乙醯丙酸2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸甲酯2-單氯乙酸鹽,5-胺基乙醯丙酸甲酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸甲酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸乙酯2-單氯乙酸鹽,5-胺基乙醯丙酸乙酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸乙酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸丙酯2-氯乙酸鹽,5-胺基乙醯丙酸丙酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸丙酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸丁酯2-單氯乙酸鹽,5-胺基乙醯丙酸丁酯2,2-二氯乙酸鹽,5-胺基
乙醯丙酸丁酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸戊酯2-氯乙酸鹽,5-胺基乙醯丙酸戊酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸戊酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸己酯2-氯乙酸鹽,5-胺基乙醯丙酸己酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸己酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸芐酯2-氯乙酸鹽,5-胺基乙醯丙酸芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸2-甲基芐酯2-氯乙酸鹽,5-胺基乙醯丙酸2-甲基芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸2-甲基芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸4-甲基芐酯2-氯乙酸鹽,5-胺基乙醯丙酸4-甲基芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸4-甲基芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸4-氯芐酯2-氯乙酸鹽,5-胺基乙醯丙酸4-氯芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸4-氯芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸4-硝基芐酯2-氯乙酸鹽,5-胺基乙醯丙酸4-硝基芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸4-硝基芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸4-異丙基芐酯2-氯乙酸鹽,5-胺基乙醯丙酸4-異丙基芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸4-異丙基芐酯2,2,2-三氯乙酸鹽。
在另一方面,本公開的鹽或其組合物可用於體內癌症組織檢測輔助外科醫生更有效地切除腫瘤組織,或通過檢查體液或組織進行體外診斷疾病或病症。
在一些實施方案中,體內診斷的方法包
括:向受試者施用式(I)的鹽或其組合物;待一段時間(例如1-4小時),使所述試劑充分吸收和轉化成光敏劑,將目標區域暴露於波長為約380至約440nm的光;檢測出螢光水平增強的區域。在一些實施方案中,螢光水平是螢光光譜。在一些實施方案中,螢光水平是螢光圖像。
在一些實施方案中,體外診斷受試者疾病的方法包括:受試者提供樣品,將樣品與式(I)的鹽或其組合物混合孵育;將混合物暴露於波長為約380至約440nm的光照;並將螢光水平與對照進行比較。
在一些實施方案中,樣品是體液或組織。
在一些實施方案中,樣品選自血液,尿液,精液,糞便,眼淚,痰液,脊髓液,骨髓和活檢組織。
在另一方面,本公開提供了製備本發明的鹽的方法,其包括使5-ALA或其酯與酸(例如三氯乙酸)反應。在使用鹽酸鹽作為原料的情況下,可以在使用一種鹼中和之後加入本公開所述的酸。
例如,用鹼處理5-ALA或其酯的鹽酸鹽,然後與本公開的酸反應,得到所需的鹽,如實施例1所述。
本公開產生所需鹽的另一種方法是在酸(例如三氯乙酸)存在下除去5-ALA或其酯衍生物的N-保護基。原料可以帶有N-Boc(N-叔丁氧羰基)或N-Cbz(N-芐氧羰基)保護基。因此,如實施例3和4所述,可在一鍋反應中除去保護基形成所需的鹽。該方面的起始原料是
5-N-Boc-胺基乙醯丙酸,Bn或5-N-Cbz-胺基乙醯丙酸或其相應的酯衍生物(例如5-N-Boc-胺基乙醯丙酸甲酯,5-N-Boc-胺基乙醯丙酸己酯,5-N-Cbz-胺基乙醯丙酸甲酯和5-N-Cbz-胺基乙醯基己基酯)。用於除去Cbz或Bn保護基的催化劑包括本領域已知的鈀,鉑,Raney鎳等。
在一些實施方案中,製備5-胺基乙醯丙酸鹽或其衍生物鹽的方法包括:提供N-保護基-5-胺基乙醯丙酸或其衍生物的溶液;加入氫化催化劑,H2和X-COOH以提供5-胺基乙醯丙酸鹽或其衍生物的鹽。
X選自氫,-CY1R1R2,-CY1Y2R1和-CY1Y2Y3。Y1,Y2和Y3獨立地選自F,Cl,Br和I。R1和R2獨立地選自氫,未取代或取代的烷基,未取代或取代的烯基,未取代或取代的炔基,未取代或取代的碳環,未取代或取代的C6-12芳基,未取代或取代的3-12元雜環,以及未取代或取代的5-12元雜芳基。R1和R2可以與其所連接的原子或原子結合形成未取代或取代的C3-12環烷基,未取代或取代的3-至12-元雜環,未取代或取代的C6-12芳基,或未取代或取代的5-至12元雜芳基。
在一些實施方案中,保護基是芐氧羰基。在一些實施方案中,氫化催化劑是鈀碳。
本公開提供的另一方法是離子交換技術,是本領域公知的成鹽的標準方法。可以使用酸性或鹼性離子交換樹脂,優選鹼性離子交換樹脂如Amberlyst A26(OH)。當起始原料為鹽形式如鹽酸鹽(例如5-ALA甲酯鹽
酸鹽)時,Cl-可以交換鹼性離子如OH-,所得洗脫液與本公開的酸混合,產生目標鹽。通常,離子交換過程包括通過填充有強鹼性離子交換樹脂Amberlyst A26(OH)的柱來洗脫5-ALA鹽溶液以除去Cl-,並依次將洗脫液與本公開的酸混合。或者,鹼性離子交換樹脂[如Amberlyst A26(OH)]和5-ALA酯鹽酸鹽在溶劑中攪拌,除去樹脂後,將本公開的酸加入濾液中製得目標鹽。這些樹脂是市售的,操作是本領域公知的。
製備本公開的鹽的起始原料可商購或可通過文獻公開的方法製備。本公開的反應可以在一種或混合溶劑中進行,如丙酮,甲醇,乙醇,丙醇,異丙醇,丁醇,異丁醇,二氯甲烷,氯仿,乙酸乙酯,乙醚,己烷,石油醚,四氫呋喃,N,N-二甲基甲醯胺或二甲基亞碸等,是本領域公知的。本公開的新鹽可通過使用上述溶劑或混合溶劑進行結晶或研磨純化。反應溫度為約-15至約100℃,可根據所用溶劑和反應選擇出最佳條件。
在一些實施方案中,製備5-胺基乙醯丙酸或其衍生物的鹽的方法包括:使5-胺基乙醯丙酸或其衍生物通過樹脂;洗脫液與X-COOH混合,得到5-胺基乙醯丙酸或其衍生物的鹽。X選自氫,-CY1R1R2,-CY1Y2R1和-CY1Y2Y3。Y1,Y2和Y3獨立地選自F,Cl,Br和I。R1和R2獨立地選自氫,未取代或取代的烷基,未取代或取代的烯基,未取代或取代的炔基,未取代或取代的碳環,未取代或取代的C6-12芳基,未取代或取代的3-12元雜環,以及
未取代或取代的5-12元雜芳基。R1和R2可以與所連接的一個或多個原子結合成未取代或取代的C3-12環烷基,未取代或取代的3-12元雜環,未取代或取代的C6-12芳基,或未取代或取代的5-12元雜芳基。
在一些實施方案中,樹脂是鹼性離子交換樹脂。
以下實施例是對本公開的方法和組成的說明,說明是非限制性的。
實施例1:5-胺基乙醯丙酸甲酯三氯乙酸鹽(5-MAL TCA)。
向乙酸乙酯(50mL)和水(20mL)中加入5-胺基乙醯丙酸甲酯鹽酸鹽(1.8g,10mmol)和NaHCO3(1.7g,20mmol)。將游離鹼萃取至有機層,水層用乙酸乙酯萃取兩次(30mL×2)。合併的乙酸乙酯溶液用Na2SO4乾燥。過濾並向濾液加入三氯乙酸(1.6g,10mmol),將溶液濃縮至乾,得到5-MAL TCA白色固體(1.7g,55%)。1HNMR(D2O,360MHz)δ ppm:2.62(t,J=6Hz,2H),2.82(t,j=6Hz,2H),3.60(s,3H),4.03(s,2H)。
實施例2:5-胺基乙醯丙酸己酯三氯乙酸鹽(5-HAL TCA)。
將5-胺基乙醯丙酸己酯鹽酸鹽(2.5g,
10mmol)溶於50%乙醇水溶液(10mL),該溶液通過Amberlyst 26(OH)(5g)層析柱,並用50%乙醇水溶液(20mL)洗滌,流出液加至三氯乙酸溶液(1.6g,10mmol)的乙醇(5mL)溶液。將合併的洗脫液蒸發至乾,得到白色固體5-HALTCA(2.1g,56%)。1HNMR(D2O,360MHz)δ ppm:0.77(t,J=6Hz,3H),1.21(br,6H)。1.53(m,2H),2.62(t,j=6Hz),2H),2.83(t,J=6Hz,2H),4.03(m,4H)。
實施例3:5-胺基乙醯丙酸三氯乙酸鹽(5-ALA TCA)。
向5-N-Cbz-胺基乙醯丙酸(2.7g,10mmol)的甲醇(35mL)溶液中加入鈀碳(10%,0.5g)和三氯乙酸(1.6g,10mmol)。將反應在H2下攪拌24小時。將反應溶液過濾並濃縮,得到5-ALA TCA白色固體(2.7g,92%)。1HNMR(D2O,360MHz)δ ppm:2.65(t,J=6Hz,2H),2.85(t,J=6Hz,2H),4.03(s,2H)。
實施例4:5-胺基乙醯丙酸乙酯三氯乙酸鹽(5-EAL TCA)。
向5-N-Boc-胺基乙醯丙酸乙酯(2.6g,10mmol)的四氫呋喃(20mL)溶液中加入三氯乙酸(1.6g,10mmol)。將反應在60℃下攪拌2小時。濃縮反應溶液得到5-胺基乙醯丙酸乙酯TCA的白色固體(2.5g,78%)。1HNMR(D2O,360MHz)δ ppm:1.23(t,J=7Hz,3H)。2.64(t,J=6Hz,2H),2.83(t,J=6Hz,2H),4.03(m,4H)。
本公開的以下鹽可用實施例1至4中所述的
方法製備:5-胺基乙醯丙酸2-單氯乙酸鹽,5-胺基乙醯丙酸2,2-二氯乙酸鹽,5-胺基乙醯丙酸2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸甲酯2-單氯乙酸鹽,5-胺基乙醯丙酸甲酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸甲酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸乙酯2-單氯乙酸鹽,5-胺基乙醯丙酸乙酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸乙酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸丙酯2-單氯乙酸鹽,5-胺基乙醯丙酸丙酯2,2,-二氯乙酸鹽,5-胺基乙醯丙酸丙酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸丁酯2-單氯乙酸鹽,5-胺基乙醯丙酸丁酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸丁酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸戊酯2-氯乙酸鹽,5-胺基乙醯丙酸戊酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸戊酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸己酯2-一氯乙酸鹽,5-胺基乙醯丙酸己酯2,2-二氯乙酸鹽和5-胺基乙醯丙酸己酯2,2,2-三氯乙酸鹽。
本公開的以下鹽可用實施例1,2和4中所述的方法製備:5-胺基乙醯丙酸芐酯2-單氯乙酸鹽,5-胺基乙醯丙酸芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸2-甲基芐酯2-單氯乙酸鹽,5-胺基乙醯丙酸2-甲基芐酯2,2-二氯乙酸鹽,2-胺基乙醯丙酸2-甲基芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸4-甲基芐酯2-單氯乙酸鹽,5-胺基乙醯丙酸4-甲基芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸4-甲基芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸4-氯芐酯2-單氯乙酸鹽,5-胺基乙醯丙酸4-氯芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸4-氯芐酯2,2,2-
三氯乙酸鹽,5-胺基乙醯丙酸4-硝基芐酯2-單氯乙酸鹽,5-胺基乙醯丙酸4-硝基芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸4-硝基芐酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸4-異丙基芐酯2-單氯乙酸鹽,5-胺基乙醯丙酸4-異丙基芐酯2,2-二氯乙酸鹽,5-胺基乙醯丙酸4-異丙基芐酯2,2,2-三氯乙酸鹽。
實施例5:吸濕性測定
用樣品重量變化測定了本公開所述鹽的吸濕性能。將測定樣品(0.2-0.4克)放置在濕度為70-85%的密閉容器中,室溫24小時後測定樣品的重量變化。5-ALA,5-MAL和5-HAL的鹽酸鹽以及5-ALA TCA都有吸濕性,它們的重量增加在25~75%。並且這些樣品由於潮解而變成液體。5-HAL TCA的重量保持不變,5-MAL TCA的重量增加最小(<5%),這兩個樣品的外觀均未變化,為晶體固體。結果表明,5-MAL TCA和5-HAL TCA具有抗濕性,是製造和儲存中質量控制所需的有利性能,以減少由吸濕性引起的降解。
實施例6:潛在的皮膚刺激/不適的測定
採用對舌表面的刺激測定了本公開所述鹽潛在的皮膚刺激/不適。將3毫克樣品放置受試者舌頭表面,3到5分鐘之後進行評估。結果表明,5-胺基酮戊酸(或酯)的三氯乙酸鹽引起的刺激/不適低於其相對應的鹽酸鹽(表1,4名參與者)。
實施例7:誘導癌細胞中生成PpIX的測定。
將測試樣品用無菌鹽水溶解至濃度為100mM作為儲備溶液。在測試前用培養基或磷酸鹽緩衝溶液(PBS)將儲備溶液稀釋至所需濃度。
衍生自人肺癌的A549細胞(ATCC)在含有4.5g/L葡萄糖,10%FCS和青黴素/鏈黴素的F12培養基(Gibco)中於37℃和6% CO2的潮濕環境中培養。在測試24小時之前將細胞以5×104/ml接種到48孔或96孔培養板中。測試前用PBS洗細胞兩次,加入含有測試化合物的新鮮培養液,每個測定為3個復孔。細胞孵育4,8或24小時後除去培養液,用PBS洗細胞兩次,測定PpIX生成含量的激發光源為360±40納米,檢測光源為620±40納米(CytoFluor Series 4000,Multi-Well Plate Reader,PerSeptive Biosystems,Framingham,MA,USA)。
觀察到本公開的鹽在細胞上誘導產生螢光的活性,並且與相應的鹽酸鹽誘導細胞產生螢光的活性相似(表2)。
實施例9:溶液製劑1。
將5-HAL TCA(250mg)溶於0.9%氯化鈉水溶液中(5mL)以形成5% 5-HAL TCA溶液。可根據不同的治療目的,使用不同的緩衝液(例如PBS)製備相應的溶液製劑。
實施例10:溶液製劑2。
將5-HAL TCA(250mg)溶解在含有三氯乙酸(100mg)的0.9%氯化鈉水溶液中(5mL)得到含有2%三氯乙
酸的5% 5-HAL TCA溶液製劑。
實施例11.凝膠製劑1。
在攪拌下將羥乙基纖維素凝膠(4.37g,1-2%,MW725,000或250,000)加入到5-ALA TCA(630mg)中,得到透明的126mg/g5-ALA TCA凝膠製劑。
實施例12:凝膠製劑2。
將含有TCA(50mg)的羥乙基纖維素凝膠(4.37g,1-2%,MW725,000或250,000)加入到5-ALA TCA(630mg)中,攪拌均勻混合得到含有1% TCA的125mg/g5-ALA TCA透明凝膠製劑。
實施例13:乳霜製劑1。
將5-MAL TCA(1.5g)與Ung.Merck均勻混合(8.5g),得到150mg/g的5-MAL TCA的白色至淡黃色乳霜製劑。
實施例14:乳霜製劑2。
將5-MAL TCA(1.5g)與Cetaphil@(8.2g)和TCA(0.3g)均勻混合,得到含3% TCA的150mg/g白色至淺黃色5-MAL TCA乳霜製劑。
實施例15:乳霜劑製劑3。
將5-MAL TCA(1g)與含有1% DMAO的Cetaphil@(9g)均勻混合,得到含有1% DMSO的0.1g/g的5-MAL TCA乳霜製劑。
5-ALA‧‧‧5-胺基乙醯丙酸,或5-胺基酮戊酸
Boc‧‧‧叔丁氧羰基
Bn‧‧‧芐基
Cbz‧‧‧芐氧羰基
CDTA‧‧‧反式-1,2-環己烷二胺四乙酸
DMSO‧‧‧二甲基亞碸
EDTA‧‧‧乙二胺四乙酸
5-HAL‧‧‧5-胺基乙醯丙酸己酯,或5-胺基酮戊酸己酯
HCl‧‧‧鹽酸
5-MAL‧‧‧5-胺基乙醯丙酸甲酯,或5-胺基酮戊酸甲酯
PDT‧‧‧光動力學療法
PDD‧‧‧光動力學診斷
PpIX‧‧‧原卟啉IX
PBS‧‧‧磷酸緩衝鹽水
TCA‧‧‧三氯乙酸
Claims (11)
- 一種具有通式(I)的鹽化合物,H2NCH2COCH2CH2COOR˙Cl3C-COOH (I)其中R選自氫,甲基,乙基,丙基,丁基,戊基,己基,第二丙基,第二丁基,第三丁基,第二戊基,第二己基,環丙基,環丁基,環戊基,環己基,芐基,2-甲基芐基,4-甲基芐基,4-氯芐基,2-硝基芐基,4-硝基芐基,2-異丙基芐基,4-異丙基芐基和4-氟芐基所組成的群組。
- 如申請專利範圍第1項所述的鹽化合物,其中R選自氫,甲基,己基和芐基所組成的群組。
- 如申請專利範圍第1項所述的鹽化合物,係選自5-胺基乙醯丙酸2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸甲酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸己酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸芐酯2,2,2-三氯乙酸鹽和5-胺基乙醯丙酸4-甲基芐酯2,2,2-三氯乙酸鹽所組成的群組。
- 如申請專利範圍第1項所述的鹽化合物,其中該鹽化合物係5-胺基乙醯丙酸2,2,2-三氯乙酸鹽。
- 如申請專利範圍第1項所述的鹽化合物,其中該鹽化合物係5-胺基乙醯丙酸甲酯2,2,2-三氯乙酸鹽。
- 如申請專利範圍第1項所述的鹽化合物,其中該鹽化合物係5-胺基乙醯丙酸己酯2,2,2-三氯乙酸鹽。
- 一種醫藥組合物,其含有如申請專利範圍第1項所述的鹽化合物和至少一種藥學上可接受的載體或賦形劑。
- 如申請專利範圍第7項所述的醫藥組合物,其中該鹽化合物選自5-胺基乙醯丙酸2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸甲酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸己酯2,2,2-三氯乙酸鹽,5-胺基乙醯丙酸芐酯2,2,2-三氯乙酸鹽和5-胺基乙醯丙酸4-甲基芐酯2,2,2-三氯乙酸鹽所組成的群組。
- 如申請專利範圍第7項所述的醫藥組合物,其中該鹽化合物係5-胺基乙醯丙酸2,2,2-三氯乙酸鹽。
- 如申請專利範圍第7項所述的醫藥組合物,其中該鹽化合物係5-胺基乙醯丙酸甲酯2,2,2-三氯乙酸鹽。
- 如申請專利範圍第7項所述的醫藥組合物,其中該鹽化合物係5-胺基乙醯丙酸已酯2,2,2-三氯乙酸鹽。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662286977P | 2016-01-26 | 2016-01-26 | |
US62/286,977 | 2016-01-26 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201731811A TW201731811A (zh) | 2017-09-16 |
TWI736577B true TWI736577B (zh) | 2021-08-21 |
Family
ID=57493289
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW106102897A TWI736577B (zh) | 2016-01-26 | 2017-01-25 | 5-胺基乙醯丙酸和其衍生物的鹽 |
Country Status (6)
Country | Link |
---|---|
US (1) | US10653653B2 (zh) |
EP (1) | EP3408254B1 (zh) |
JP (1) | JP6832358B2 (zh) |
CN (2) | CN106187793A (zh) |
TW (1) | TWI736577B (zh) |
WO (1) | WO2017132178A2 (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108937864A (zh) * | 2018-06-05 | 2018-12-07 | 四川大学 | 口腔黏膜诱发荧光检测诊断仪 |
KR20210142105A (ko) | 2019-02-13 | 2021-11-24 | 알페이오스 메디컬, 인코포레이티드 | 비침습적 초음파역학 요법 |
US20220218826A1 (en) * | 2019-05-15 | 2022-07-14 | Daniela Ines LEON GARRIDO | Composition for topical use for photodynamic therapy |
KR102265592B1 (ko) * | 2020-10-29 | 2021-06-17 | 김진왕 | 5-아미노레불린산 수화염화물을 포함하는 조성물 |
CN114504551B (zh) * | 2020-11-16 | 2024-01-02 | 北京厚燊维康科技有限责任公司 | 可用于光动力治疗或诊断的制剂 |
JP2023553837A (ja) * | 2020-11-30 | 2023-12-26 | ソンエーエルエーセンス,インコーポレイティド | 低悪性度の腫瘍の代謝標的化 |
CN113620828A (zh) * | 2021-08-17 | 2021-11-09 | 湖南复瑞生物医药技术有限责任公司 | 一种5-氨基酮戊酸酯化物、用途和农药组合物 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1938264A (zh) * | 2004-03-26 | 2007-03-28 | 弗托库尔公司 | 5-氨基乙酰丙酸或其衍生物的酸加成盐 |
CN103889410A (zh) * | 2011-08-05 | 2014-06-25 | 奥克西冈有限公司 | 用于治疗皮肤损伤的络合的锌和α-氯羧酸化合物 |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE397731A (zh) | 1932-07-21 | |||
US5273982A (en) * | 1990-03-09 | 1993-12-28 | Hoffmann-La Roche Inc. | Acetic acid derivatives |
CN1023338C (zh) * | 1990-04-01 | 1993-12-29 | 张廷余 | 海洋波浪能发电装置 |
JP2896963B2 (ja) | 1994-11-28 | 1999-05-31 | 株式会社コスモ総合研究所 | 植物の耐塩性向上剤 |
US6492420B2 (en) | 1995-03-10 | 2002-12-10 | Photocure As | Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy |
NZ303251A (en) | 1995-03-10 | 2000-10-27 | Photocure Asa | Use of esters of 5-aminolevulinic acid as photosensitising agents in photochemotherapy |
CA2206203A1 (en) | 1997-05-27 | 1998-11-27 | University Of British Columbia | Photoactivation of endogenous porphyrins for treatment of psoriasis |
FR2769626B1 (fr) * | 1997-10-15 | 1999-12-03 | Elf Aquitaine Exploration Prod | Stabilisation de l'acide thioacetique |
DE10003620A1 (de) | 2000-01-28 | 2001-08-02 | Asat Ag Applied Science & Tech | 5-Aminolävulinsäure-Formulierung in nichtwässrigen Lösungsmitteln |
GB0018528D0 (en) | 2000-07-27 | 2000-09-13 | Photocure Asa | Compounds |
US6723750B2 (en) | 2002-03-15 | 2004-04-20 | Allergan, Inc. | Photodynamic therapy for pre-melanomas |
KR20050013125A (ko) | 2002-06-10 | 2005-02-02 | 와이어쓰 | O-데스메틸-벤라팍신의 신규한 포르메이트 염 |
US20040147501A1 (en) * | 2002-07-08 | 2004-07-29 | Dolmans Dennis E.J.G.J. | Photodynamic therapy |
WO2004093993A1 (en) | 2003-04-23 | 2004-11-04 | Qlt Inc. | Hair growth |
US20050124638A1 (en) * | 2003-12-08 | 2005-06-09 | Swayze Eric E. | Benzimidazoles and analogs thereof as antivirals |
ATE493382T1 (de) | 2004-03-30 | 2011-01-15 | Cosmo Oil Co Ltd | 5-aminolevulinsäure-phosphatsalz, verfahren zu dessen herstellung und dessen verwendung |
ATE466867T1 (de) * | 2004-11-02 | 2010-05-15 | Dsm Ip Assets Bv | Neue topisch anwendbare wirkstoffe gegen mimische und alterabedingt falten |
US20070225518A1 (en) * | 2006-03-22 | 2007-09-27 | Zvi Malik | 5-Aminolevulinic acid salts and their use |
JP5645104B2 (ja) * | 2010-05-24 | 2014-12-24 | 国立大学法人東京工業大学 | アラレマイシン誘導体 |
EP2407151B1 (en) | 2010-07-15 | 2019-10-02 | Progressare Medinvest B.V. | Composition for the treatment of skin and/or nail lesions |
US20120330216A1 (en) * | 2011-06-24 | 2012-12-27 | Saad Ibrahim Almohizea | Methods and apparatus for skin rejuvenation |
DK3461825T3 (da) * | 2011-09-30 | 2023-08-14 | C&C Res Lab | Nye heterocykliske derivater samt deres anvendelser |
JP5907357B2 (ja) * | 2011-10-12 | 2016-04-26 | Sbiファーマ株式会社 | 移植臓器生着促進剤 |
EP2880012B1 (en) * | 2012-08-03 | 2021-12-15 | Photocure ASA | Compounds |
CN103265444B (zh) * | 2013-04-24 | 2014-11-05 | 浙江大学 | 一种5-氨基乙酰丙酸磷酸盐的结晶方法 |
CN104478991B (zh) * | 2014-12-10 | 2018-06-19 | 深圳市维琪医药研发有限公司 | 一种新型多肽化合物及其制备方法和其医药应用 |
-
2016
- 2016-07-20 CN CN201610568868.0A patent/CN106187793A/zh active Pending
- 2016-07-20 CN CN202010877014.7A patent/CN112010772A/zh active Pending
-
2017
- 2017-01-24 JP JP2018538746A patent/JP6832358B2/ja active Active
- 2017-01-24 US US16/071,485 patent/US10653653B2/en active Active
- 2017-01-24 EP EP17744788.5A patent/EP3408254B1/en active Active
- 2017-01-24 WO PCT/US2017/014791 patent/WO2017132178A2/en active Application Filing
- 2017-01-25 TW TW106102897A patent/TWI736577B/zh active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1938264A (zh) * | 2004-03-26 | 2007-03-28 | 弗托库尔公司 | 5-氨基乙酰丙酸或其衍生物的酸加成盐 |
CN103889410A (zh) * | 2011-08-05 | 2014-06-25 | 奥克西冈有限公司 | 用于治疗皮肤损伤的络合的锌和α-氯羧酸化合物 |
Also Published As
Publication number | Publication date |
---|---|
US10653653B2 (en) | 2020-05-19 |
JP6832358B2 (ja) | 2021-02-24 |
EP3408254A4 (en) | 2019-01-30 |
WO2017132178A2 (en) | 2017-08-03 |
CN106187793A (zh) | 2016-12-07 |
EP3408254B1 (en) | 2020-11-04 |
CN112010772A (zh) | 2020-12-01 |
EP3408254A2 (en) | 2018-12-05 |
JP2019517990A (ja) | 2019-06-27 |
TW201731811A (zh) | 2017-09-16 |
WO2017132178A3 (en) | 2017-12-07 |
US20190022044A1 (en) | 2019-01-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI736577B (zh) | 5-胺基乙醯丙酸和其衍生物的鹽 | |
ES2639021T3 (es) | Sales de adición de ácido del ácido 5-aminolevulínico o sus derivados | |
JP5010088B2 (ja) | 光化学治療における光増感剤としての5−アミノレブリン酸のエステル | |
CN1137087C (zh) | 用作光化学疗法中的光致敏剂的5-氨基酮戊酸的酯 | |
US7247655B2 (en) | Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy | |
KR100628548B1 (ko) | 감광제 및 그 제조방법 | |
BRPI0212172B1 (pt) | Agente fotossensibilizante, processo para a preparação de um agente fotossensibilizante, composição farmacêutica, usos de um agente fotossensibilizante ou de um sal farmaceuticamente aceitável do mesmo, e de um agente fotossensibilizante ou de um sal farmaceuticamente aceitável do mesmo e de uma molécula de transferência, métodos para a introdução de uma molécula de transferência no citosol de uma célula in vitro e para diagnose in vitro de anormalidades ou distúrbios através da análise de uma amostra de fluido ou tecido do corpo de um paciente, produto, e, kit para uso em fotoquimioterapia de distúrbios ou anormalidades de superfícies externas ou internas do corpo | |
US20050107471A1 (en) | New esters of 5-aminolevulinic acid and their use as photosensitizing compounds in photochemotherapy | |
RU2191010C2 (ru) | Сложные эфиры 5-аминолевулиновой кислоты в качестве фотосенсибилизаторов в фотохимиотерапии | |
RomiszewskA et al. | The use of 5-aminolevulinic acid and its derivatives in photodynamic therapy and diagnosis |