CN113039180A - 3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐或其药学上可接受的溶剂化物 - Google Patents
3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐或其药学上可接受的溶剂化物 Download PDFInfo
- Publication number
- CN113039180A CN113039180A CN201980076050.9A CN201980076050A CN113039180A CN 113039180 A CN113039180 A CN 113039180A CN 201980076050 A CN201980076050 A CN 201980076050A CN 113039180 A CN113039180 A CN 113039180A
- Authority
- CN
- China
- Prior art keywords
- tetrahydropyridin
- anatabine
- pyridine
- compound
- polymorphic form
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- YAXCSXPWFPMOGI-UHFFFAOYSA-N pentanedioic acid 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine Chemical compound OC(=O)CCCC(O)=O.C1NC(CC=C1)c1cccnc1 YAXCSXPWFPMOGI-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 239000012453 solvate Substances 0.000 title claims abstract description 17
- 239000013078 crystal Substances 0.000 claims abstract description 95
- 206010061218 Inflammation Diseases 0.000 claims abstract description 33
- 230000004054 inflammatory process Effects 0.000 claims abstract description 33
- 238000011282 treatment Methods 0.000 claims abstract description 30
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 18
- 230000002265 prevention Effects 0.000 claims abstract description 12
- SOPPBXUYQGUQHE-UHFFFAOYSA-N 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine Chemical compound C1C=CCNC1C1=CC=CN=C1 SOPPBXUYQGUQHE-UHFFFAOYSA-N 0.000 claims description 149
- SOPPBXUYQGUQHE-JTQLQIEISA-N Anatabine Chemical group C1C=CCN[C@@H]1C1=CC=CN=C1 SOPPBXUYQGUQHE-JTQLQIEISA-N 0.000 claims description 127
- 150000001875 compounds Chemical class 0.000 claims description 111
- 239000000203 mixture Substances 0.000 claims description 73
- 239000008194 pharmaceutical composition Substances 0.000 claims description 68
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 65
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 46
- 239000002904 solvent Substances 0.000 claims description 26
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 23
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 claims description 21
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 18
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 18
- 229960002715 nicotine Drugs 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000000443 aerosol Substances 0.000 claims description 14
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 14
- 208000024827 Alzheimer disease Diseases 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 229960003920 cocaine Drugs 0.000 claims description 7
- 229940112141 dry powder inhaler Drugs 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 206010043778 thyroiditis Diseases 0.000 claims description 5
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 claims description 3
- 206010057852 Nicotine dependence Diseases 0.000 claims description 3
- 208000025569 Tobacco Use disease Diseases 0.000 claims description 3
- 229960002069 diamorphine Drugs 0.000 claims description 3
- 240000004308 marijuana Species 0.000 claims 1
- 206010010904 Convulsion Diseases 0.000 description 83
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 57
- 208000035475 disorder Diseases 0.000 description 41
- 241000208125 Nicotiana Species 0.000 description 38
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 37
- 229930013930 alkaloid Natural products 0.000 description 29
- 206010015037 epilepsy Diseases 0.000 description 27
- 239000000523 sample Substances 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 230000001404 mediated effect Effects 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 230000000694 effects Effects 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 201000010099 disease Diseases 0.000 description 16
- 208000024891 symptom Diseases 0.000 description 16
- 150000003797 alkaloid derivatives Chemical class 0.000 description 15
- 239000007788 liquid Substances 0.000 description 15
- -1 lithium aluminum hydride Chemical compound 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- 230000002757 inflammatory effect Effects 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- 239000000796 flavoring agent Substances 0.000 description 12
- 206010061334 Partial seizures Diseases 0.000 description 11
- 102000003923 Protein Kinase C Human genes 0.000 description 11
- 108090000315 Protein Kinase C Proteins 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- 239000003112 inhibitor Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 238000002560 therapeutic procedure Methods 0.000 description 11
- 102000010909 Monoamine Oxidase Human genes 0.000 description 10
- 108010062431 Monoamine oxidase Proteins 0.000 description 10
- 208000028311 absence seizure Diseases 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 239000007937 lozenge Substances 0.000 description 10
- 241000218236 Cannabis Species 0.000 description 9
- 208000029560 autism spectrum disease Diseases 0.000 description 9
- 239000012458 free base Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 235000019505 tobacco product Nutrition 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 8
- 230000001419 dependent effect Effects 0.000 description 8
- 239000003571 electronic cigarette Substances 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 208000024714 major depressive disease Diseases 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 238000001179 sorption measurement Methods 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 208000034308 Grand mal convulsion Diseases 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 235000013355 food flavoring agent Nutrition 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 238000013518 transcription Methods 0.000 description 7
- 230000035897 transcription Effects 0.000 description 7
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 7
- 229940045997 vitamin a Drugs 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 208000002091 Febrile Seizures Diseases 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 206010044565 Tremor Diseases 0.000 description 6
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 230000002411 adverse Effects 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- 235000013305 food Nutrition 0.000 description 6
- 230000000926 neurological effect Effects 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- MTXSIJUGVMTTMU-JTQLQIEISA-N (S)-anabasine Chemical compound N1CCCC[C@H]1C1=CC=CN=C1 MTXSIJUGVMTTMU-JTQLQIEISA-N 0.000 description 5
- MYKUKUCHPMASKF-VIFPVBQESA-N (S)-nornicotine Chemical compound C1CCN[C@@H]1C1=CC=CN=C1 MYKUKUCHPMASKF-VIFPVBQESA-N 0.000 description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- 206010003805 Autism Diseases 0.000 description 5
- 208000020706 Autistic disease Diseases 0.000 description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 5
- 206010019233 Headaches Diseases 0.000 description 5
- 201000006792 Lennox-Gastaut syndrome Diseases 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- MYKUKUCHPMASKF-UHFFFAOYSA-N Nornicotine Natural products C1CCNC1C1=CC=CN=C1 MYKUKUCHPMASKF-UHFFFAOYSA-N 0.000 description 5
- 208000018737 Parkinson disease Diseases 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000004075 alteration Effects 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000003111 delayed effect Effects 0.000 description 5
- 229910052805 deuterium Inorganic materials 0.000 description 5
- 230000000632 dystonic effect Effects 0.000 description 5
- 231100000869 headache Toxicity 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 238000004255 ion exchange chromatography Methods 0.000 description 5
- 230000002045 lasting effect Effects 0.000 description 5
- 230000033001 locomotion Effects 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 230000035807 sensation Effects 0.000 description 5
- 235000019615 sensations Nutrition 0.000 description 5
- 238000002411 thermogravimetry Methods 0.000 description 5
- 235000005282 vitamin D3 Nutrition 0.000 description 5
- 239000011647 vitamin D3 Substances 0.000 description 5
- 229940021056 vitamin d3 Drugs 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 4
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 4
- 206010003830 Automatism Diseases 0.000 description 4
- 208000032841 Bulimia Diseases 0.000 description 4
- 206010006550 Bulimia nervosa Diseases 0.000 description 4
- 208000027691 Conduct disease Diseases 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 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 4
- 208000020401 Depressive disease Diseases 0.000 description 4
- 206010013754 Drug withdrawal syndrome Diseases 0.000 description 4
- 208000030814 Eating disease Diseases 0.000 description 4
- 208000002877 Epileptic Syndromes Diseases 0.000 description 4
- 208000019454 Feeding and Eating disease Diseases 0.000 description 4
- 208000011688 Generalised anxiety disease Diseases 0.000 description 4
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 4
- 208000037158 Partial Epilepsies Diseases 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 206010041250 Social phobia Diseases 0.000 description 4
- 208000006045 Spondylarthropathies Diseases 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 208000028552 Treatment-Resistant Depressive disease Diseases 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 208000003554 absence epilepsy Diseases 0.000 description 4
- 229930014345 anabasine Natural products 0.000 description 4
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 4
- 208000025748 atypical depressive disease Diseases 0.000 description 4
- 235000013361 beverage Nutrition 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 235000015218 chewing gum Nutrition 0.000 description 4
- 208000022371 chronic pain syndrome Diseases 0.000 description 4
- 235000019504 cigarettes Nutrition 0.000 description 4
- 206010009887 colitis Diseases 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000000113 differential scanning calorimetry Methods 0.000 description 4
- 235000014632 disordered eating Nutrition 0.000 description 4
- 208000024732 dysthymic disease Diseases 0.000 description 4
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 208000029364 generalized anxiety disease Diseases 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 208000013403 hyperactivity Diseases 0.000 description 4
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 4
- 208000027866 inflammatory disease Diseases 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 201000003995 melancholia Diseases 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- 201000003631 narcolepsy Diseases 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229940005483 opioid analgesics Drugs 0.000 description 4
- 208000019906 panic disease Diseases 0.000 description 4
- 208000030062 persistent idiopathic facial pain Diseases 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 229960004063 propylene glycol Drugs 0.000 description 4
- 235000013772 propylene glycol Nutrition 0.000 description 4
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 4
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 230000001953 sensory effect Effects 0.000 description 4
- 239000007909 solid dosage form Substances 0.000 description 4
- 201000005671 spondyloarthropathy Diseases 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 208000005809 status epilepticus Diseases 0.000 description 4
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 4
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 229940095064 tartrate Drugs 0.000 description 4
- 201000008914 temporal lobe epilepsy Diseases 0.000 description 4
- 230000001256 tonic effect Effects 0.000 description 4
- 229940088594 vitamin Drugs 0.000 description 4
- 229930003231 vitamin Natural products 0.000 description 4
- 235000013343 vitamin Nutrition 0.000 description 4
- 239000011782 vitamin Substances 0.000 description 4
- KRQUFUKTQHISJB-YYADALCUSA-N 2-[(E)-N-[2-(4-chlorophenoxy)propoxy]-C-propylcarbonimidoyl]-3-hydroxy-5-(thian-3-yl)cyclohex-2-en-1-one Chemical compound CCC\C(=N/OCC(C)OC1=CC=C(Cl)C=C1)C1=C(O)CC(CC1=O)C1CCCSC1 KRQUFUKTQHISJB-YYADALCUSA-N 0.000 description 3
- 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 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 3
- 206010003571 Astrocytoma Diseases 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 3
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 3
- 208000033001 Complex partial seizures Diseases 0.000 description 3
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 3
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- 108010036949 Cyclosporine Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 3
- 208000007882 Gastritis Diseases 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 3
- 102000004495 STAT3 Transcription Factor Human genes 0.000 description 3
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 3
- 206010040703 Simple partial seizures Diseases 0.000 description 3
- 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 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 206010043994 Tonic convulsion Diseases 0.000 description 3
- 206010047115 Vasculitis Diseases 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 230000032683 aging Effects 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 238000005102 attenuated total reflection Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 235000012206 bottled water Nutrition 0.000 description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 3
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- 229960004106 citric acid Drugs 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 235000019788 craving Nutrition 0.000 description 3
- 229930182912 cyclosporin Natural products 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000003795 desorption Methods 0.000 description 3
- 235000015872 dietary supplement Nutrition 0.000 description 3
- 229960003638 dopamine Drugs 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000013265 extended release Methods 0.000 description 3
- 210000003414 extremity Anatomy 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 229940043355 kinase inhibitor Drugs 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 201000005962 mycosis fungoides Diseases 0.000 description 3
- 230000004770 neurodegeneration Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 210000001152 parietal lobe Anatomy 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- HQLWPSADLWACNE-UHFFFAOYSA-N pentanedioic acid;pyridine Chemical compound C1=CC=NC=C1.OC(=O)CCCC(O)=O HQLWPSADLWACNE-UHFFFAOYSA-N 0.000 description 3
- 230000004962 physiological condition Effects 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 150000003077 polyols Chemical class 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000001757 thermogravimetry curve Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- FCSIYFXMBFVWPD-PPHPATTJSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid 3-[(2S)-1,2,3,6-tetrahydropyridin-2-yl]pyridine Chemical compound C1C=CCN[C@@H]1C1=CC=CN=C1.OC(=O)CC(O)(C(O)=O)CC(O)=O FCSIYFXMBFVWPD-PPHPATTJSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 208000008882 Benign Neonatal Epilepsy Diseases 0.000 description 2
- 206010004593 Bile duct cancer Diseases 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 102000019025 Calcium-Calmodulin-Dependent Protein Kinases Human genes 0.000 description 2
- 108010026870 Calcium-Calmodulin-Dependent Protein Kinases Proteins 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 201000001913 Childhood absence epilepsy Diseases 0.000 description 2
- 244000223760 Cinnamomum zeylanicum Species 0.000 description 2
- 206010009346 Clonus Diseases 0.000 description 2
- 208000015943 Coeliac disease Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000032274 Encephalopathy Diseases 0.000 description 2
- 206010014733 Endometrial cancer Diseases 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 description 2
- 208000024658 Epilepsy syndrome Diseases 0.000 description 2
- 244000004281 Eucalyptus maculata Species 0.000 description 2
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- 201000009010 Frontal lobe epilepsy Diseases 0.000 description 2
- 240000001238 Gaultheria procumbens Species 0.000 description 2
- 235000007297 Gaultheria procumbens Nutrition 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
- 208000009329 Graft vs Host Disease Diseases 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010021750 Infantile Spasms Diseases 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 206010023825 Laryngeal cancer Diseases 0.000 description 2
- 208000036626 Mental retardation Diseases 0.000 description 2
- 235000014749 Mentha crispa Nutrition 0.000 description 2
- 244000246386 Mentha pulegium Species 0.000 description 2
- 235000016257 Mentha pulegium Nutrition 0.000 description 2
- 244000078639 Mentha spicata Species 0.000 description 2
- 235000004357 Mentha x piperita Nutrition 0.000 description 2
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 2
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 2
- 208000002033 Myoclonus Diseases 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 2
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 2
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- 208000018262 Peripheral vascular disease Diseases 0.000 description 2
- 206010034759 Petit mal epilepsy Diseases 0.000 description 2
- 241000241413 Propolis Species 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 244000061456 Solanum tuberosum Species 0.000 description 2
- 235000002595 Solanum tuberosum Nutrition 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 239000004376 Sucralose Substances 0.000 description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
- 208000003443 Unconsciousness Diseases 0.000 description 2
- 206010047163 Vasospasm Diseases 0.000 description 2
- 229930003427 Vitamin E Natural products 0.000 description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 2
- 201000006791 West syndrome Diseases 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 2
- 210000004727 amygdala Anatomy 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 201000007197 atypical autism Diseases 0.000 description 2
- 230000002567 autonomic effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229940112822 chewing gum Drugs 0.000 description 2
- 235000017803 cinnamon Nutrition 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 230000002566 clonic effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 201000005108 complex partial epilepsy Diseases 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 230000002920 convulsive effect Effects 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 201000009028 early myoclonic encephalopathy Diseases 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 206010014599 encephalitis Diseases 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 238000012494 forced degradation Methods 0.000 description 2
- 210000001652 frontal lobe Anatomy 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 208000024908 graft versus host disease Diseases 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 235000001050 hortel pimenta Nutrition 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 206010023841 laryngeal neoplasm Diseases 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229940041616 menthol Drugs 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 229960002216 methylparaben Drugs 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 239000008368 mint flavor Substances 0.000 description 2
- 238000001565 modulated differential scanning calorimetry Methods 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 230000003959 neuroinflammation Effects 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- 208000008494 pericarditis Diseases 0.000 description 2
- VGEREEWJJVICBM-UHFFFAOYSA-N phloretin Chemical compound C1=CC(O)=CC=C1CCC(=O)C1=C(O)C=C(O)C=C1O VGEREEWJJVICBM-UHFFFAOYSA-N 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 230000036544 posture Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 229940069949 propolis Drugs 0.000 description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
- 229960003415 propylparaben Drugs 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 230000001172 regenerating effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 229960000342 retinol acetate Drugs 0.000 description 2
- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical compound CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 description 2
- 235000019173 retinyl acetate Nutrition 0.000 description 2
- 239000011770 retinyl acetate Substances 0.000 description 2
- 229960002477 riboflavin Drugs 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000000779 smoke Substances 0.000 description 2
- 230000005586 smoking cessation Effects 0.000 description 2
- 230000000391 smoking effect Effects 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 102000009076 src-Family Kinases Human genes 0.000 description 2
- 108010087686 src-Family Kinases Proteins 0.000 description 2
- 238000013097 stability assessment Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 2
- 235000019408 sucralose Nutrition 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 229960001967 tacrolimus Drugs 0.000 description 2
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 210000003478 temporal lobe Anatomy 0.000 description 2
- 230000004797 therapeutic response Effects 0.000 description 2
- 238000002207 thermal evaporation Methods 0.000 description 2
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 2
- 229960003495 thiamine Drugs 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- 235000010215 titanium dioxide Nutrition 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 239000001069 triethyl citrate Substances 0.000 description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 2
- 235000013769 triethyl citrate Nutrition 0.000 description 2
- 208000019553 vascular disease Diseases 0.000 description 2
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 2
- 235000019165 vitamin E Nutrition 0.000 description 2
- 239000011709 vitamin E Substances 0.000 description 2
- 229940046009 vitamin E Drugs 0.000 description 2
- 229940011671 vitamin b6 Drugs 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- ZWTDXYUDJYDHJR-UHFFFAOYSA-N (E)-1-(2,4-dihydroxyphenyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one Natural products OC1=CC(O)=CC=C1C=CC(=O)C1=CC=C(O)C=C1O ZWTDXYUDJYDHJR-UHFFFAOYSA-N 0.000 description 1
- 229930182840 (S)-nicotine Natural products 0.000 description 1
- JLOXTZFYJNCPIS-FYWRMAATSA-N (z)-3-amino-3-(4-aminophenyl)sulfanyl-2-[2-(trifluoromethyl)phenyl]prop-2-enenitrile Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(\C#N)=C(/N)SC1=CC=C(N)C=C1 JLOXTZFYJNCPIS-FYWRMAATSA-N 0.000 description 1
- MMWRGWQTAMNAFC-UHFFFAOYSA-N 1,2-dihydropyridine Chemical class C1NC=CC=C1 MMWRGWQTAMNAFC-UHFFFAOYSA-N 0.000 description 1
- WEEFNMFMNMASJY-UHFFFAOYSA-M 1,2-dimethoxy-12-methyl-[1,3]benzodioxolo[5,6-c]phenanthridin-12-ium;chloride Chemical compound [Cl-].C1=C2OCOC2=CC2=CC=C3C4=CC=C(OC)C(OC)=C4C=[N+](C)C3=C21 WEEFNMFMNMASJY-UHFFFAOYSA-M 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- HBOMLICNUCNMMY-KJFJCRTCSA-N 1-[(4s,5s)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1C1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-KJFJCRTCSA-N 0.000 description 1
- PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- QFWCYNPOPKQOKV-UHFFFAOYSA-N 2-(2-amino-3-methoxyphenyl)chromen-4-one Chemical compound COC1=CC=CC(C=2OC3=CC=CC=C3C(=O)C=2)=C1N QFWCYNPOPKQOKV-UHFFFAOYSA-N 0.000 description 1
- LPHWCAUEPAUFHZ-UHFFFAOYSA-N 3,6-Dihydropyridine Chemical class C1C=CCN=C1 LPHWCAUEPAUFHZ-UHFFFAOYSA-N 0.000 description 1
- SOPPBXUYQGUQHE-SNVBAGLBSA-N 3-[(2r)-1,2,3,6-tetrahydropyridin-2-yl]pyridine Chemical compound C1C=CCN[C@H]1C1=CC=CN=C1 SOPPBXUYQGUQHE-SNVBAGLBSA-N 0.000 description 1
- NEBCAMAQXZIVRE-UHFFFAOYSA-N 5-(methoxymethyl)-4-[2,3,4-trihydroxy-6-(methoxymethyl)phenyl]benzene-1,2,3-triol Chemical compound COCC1=CC(O)=C(O)C(O)=C1C1=C(O)C(O)=C(O)C=C1COC NEBCAMAQXZIVRE-UHFFFAOYSA-N 0.000 description 1
- WHSIXKUPQCKWBY-IOSLPCCCSA-N 5-iodotubercidin Chemical compound C1=C(I)C=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O WHSIXKUPQCKWBY-IOSLPCCCSA-N 0.000 description 1
- 208000002008 AIDS-Related Lymphoma Diseases 0.000 description 1
- 102000003678 AMPA Receptors Human genes 0.000 description 1
- 108090000078 AMPA Receptors Proteins 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 241000239290 Araneae Species 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- 208000036640 Asperger disease Diseases 0.000 description 1
- 201000006062 Asperger syndrome Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000023514 Barrett esophagus Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000007204 Brain death Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 201000011057 Breast sarcoma Diseases 0.000 description 1
- 206010006417 Bronchial carcinoma Diseases 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- 102000004631 Calcineurin Human genes 0.000 description 1
- 108010042955 Calcineurin Proteins 0.000 description 1
- 241000282421 Canidae Species 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 description 1
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 240000004160 Capsicum annuum Species 0.000 description 1
- 235000008534 Capsicum annuum var annuum Nutrition 0.000 description 1
- 235000007862 Capsicum baccatum Nutrition 0.000 description 1
- 206010007279 Carcinoid tumour of the gastrointestinal tract Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 206010061040 Childhood psychosis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 206010053398 Clonic convulsion Diseases 0.000 description 1
- 206010009657 Clostridium difficile colitis Diseases 0.000 description 1
- 206010009895 Colitis ischaemic Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010010301 Confusion and disorientation Diseases 0.000 description 1
- 208000032065 Convulsion neonatal Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000009798 Craniopharyngioma Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 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 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- VDRZDTXJMRRVMF-UONOGXRCSA-N D-erythro-sphingosine Natural products CCCCCCCCCC=C[C@@H](O)[C@@H](N)CO VDRZDTXJMRRVMF-UONOGXRCSA-N 0.000 description 1
- 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 1
- 206010012335 Dependence Diseases 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 208000021994 Diffuse astrocytoma Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- AFSDNFLWKVMVRB-UHFFFAOYSA-N Ellagic acid Chemical compound OC1=C(O)C(OC2=O)=C3C4=C2C=C(O)C(O)=C4OC(=O)C3=C1 AFSDNFLWKVMVRB-UHFFFAOYSA-N 0.000 description 1
- ATJXMQHAMYVHRX-CPCISQLKSA-N Ellagic acid Natural products OC1=C(O)[C@H]2OC(=O)c3cc(O)c(O)c4OC(=O)C(=C1)[C@H]2c34 ATJXMQHAMYVHRX-CPCISQLKSA-N 0.000 description 1
- 229920002079 Ellagic acid Polymers 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014896 Enterocolitis haemorrhagic Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 208000017259 Extragonadal germ cell tumor Diseases 0.000 description 1
- 208000034347 Faecal incontinence Diseases 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 208000004262 Food Hypersensitivity Diseases 0.000 description 1
- 102000005915 GABA Receptors Human genes 0.000 description 1
- 108010005551 GABA Receptors Proteins 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 229920002148 Gellan gum Polymers 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- 208000021309 Germ cell tumor Diseases 0.000 description 1
- 241000282818 Giraffidae Species 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 241001595785 Granata Species 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 208000032759 Hemolytic-Uremic Syndrome Diseases 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010021042 Hypopharyngeal cancer Diseases 0.000 description 1
- 206010056305 Hypopharyngeal neoplasm Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000006877 Insect Bites and Stings Diseases 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 206010061252 Intraocular melanoma Diseases 0.000 description 1
- 208000009164 Islet Cell Adenoma Diseases 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010071082 Juvenile myoclonic epilepsy Diseases 0.000 description 1
- KOZFSFOOLUUIGY-SOLYNIJKSA-N K-252a Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@](C(=O)OC)(O)[C@]4(C)O1 KOZFSFOOLUUIGY-SOLYNIJKSA-N 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 206010069698 Langerhans' cell histiocytosis Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010062038 Lip neoplasm Diseases 0.000 description 1
- 229920000161 Locust bean gum Polymers 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000005777 Lupus Nephritis Diseases 0.000 description 1
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010025312 Lymphoma AIDS related Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000721701 Lynx Species 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 206010054805 Macroangiopathy Diseases 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 108010036176 Melitten Proteins 0.000 description 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 1
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010061296 Motor dysfunction Diseases 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 101001135571 Mus musculus Tyrosine-protein phosphatase non-receptor type 2 Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 206010049816 Muscle tightness Diseases 0.000 description 1
- 206010028347 Muscle twitching Diseases 0.000 description 1
- 208000021642 Muscular disease Diseases 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 201000009623 Myopathy Diseases 0.000 description 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- SBKRTALNRRAOJP-BWSIXKJUSA-N N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methylheptanamide (6S)-N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide sulfuric acid Polymers OS(O)(=O)=O.CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@@H](NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](CCN)NC1=O)[C@@H](C)O.CC[C@H](C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@@H](NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](CCN)NC1=O)[C@@H](C)O SBKRTALNRRAOJP-BWSIXKJUSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- DDBOTIGHDDUIDB-UHFFFAOYSA-N N1=CC=CC(=C1)C1N(C)CCC1.C(CCCC(=O)O)(=O)O Chemical compound N1=CC=CC(=C1)C1N(C)CCC1.C(CCCC(=O)O)(=O)O DDBOTIGHDDUIDB-UHFFFAOYSA-N 0.000 description 1
- 101000783356 Naja sputatrix Cytotoxin Proteins 0.000 description 1
- YQHMWTPYORBCMF-UHFFFAOYSA-N Naringenin chalcone Natural products C1=CC(O)=CC=C1C=CC(=O)C1=C(O)C=C(O)C=C1O YQHMWTPYORBCMF-UHFFFAOYSA-N 0.000 description 1
- 206010028729 Nasal cavity cancer Diseases 0.000 description 1
- 206010028767 Nasal sinus cancer Diseases 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 208000029726 Neurodevelopmental disease Diseases 0.000 description 1
- 102000004108 Neurotransmitter Receptors Human genes 0.000 description 1
- 108090000590 Neurotransmitter Receptors Proteins 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 206010031096 Oropharyngeal cancer Diseases 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 240000005373 Panax quinquefolius Species 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- 241001111421 Pannus Species 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- 241000282376 Panthera tigris Species 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000003937 Paranasal Sinus Neoplasms Diseases 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- 208000012202 Pervasive developmental disease Diseases 0.000 description 1
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 1
- 206010034811 Pharyngeal cancer Diseases 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000146226 Physalis ixocarpa Species 0.000 description 1
- 240000009134 Physalis philadelphica Species 0.000 description 1
- 235000002489 Physalis philadelphica Nutrition 0.000 description 1
- IIXHQGSINFQLRR-UHFFFAOYSA-N Piceatannol Natural products Oc1ccc(C=Cc2c(O)c(O)c3CCCCc3c2O)cc1O IIXHQGSINFQLRR-UHFFFAOYSA-N 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 208000010332 Plantar Fasciitis Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 201000008199 Pleuropulmonary blastoma Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 108010093965 Polymyxin B Proteins 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 206010052469 Postictal paralysis Diseases 0.000 description 1
- 208000002389 Pouchitis Diseases 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 206010036590 Premature baby Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 241000283080 Proboscidea <mammal> Species 0.000 description 1
- HDSBZMRLPLPFLQ-UHFFFAOYSA-N Propylene glycol alginate Chemical compound OC1C(O)C(OC)OC(C(O)=O)C1OC1C(O)C(O)C(C)C(C(=O)OCC(C)O)O1 HDSBZMRLPLPFLQ-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 208000003100 Pseudomembranous Enterocolitis Diseases 0.000 description 1
- 206010037128 Pseudomembranous colitis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 206010037180 Psychiatric symptoms Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 208000006289 Rett Syndrome Diseases 0.000 description 1
- 208000008938 Rhabdoid tumor Diseases 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 102000001332 SRC Human genes 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 241000270295 Serpentes Species 0.000 description 1
- 208000009359 Sezary Syndrome Diseases 0.000 description 1
- 208000021388 Sezary disease Diseases 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 240000003768 Solanum lycopersicum Species 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 102000003673 Symporters Human genes 0.000 description 1
- 108090000088 Symporters Proteins 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 208000031673 T-Cell Cutaneous 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
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 208000002240 Tennis Elbow Diseases 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- 208000000728 Thymus Neoplasms Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 208000006593 Urologic Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 201000005969 Uveal melanoma Diseases 0.000 description 1
- 229930003451 Vitamin B1 Natural products 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 229930003471 Vitamin B2 Natural products 0.000 description 1
- 229930003761 Vitamin B9 Natural products 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- MECHNRXZTMCUDQ-UHFFFAOYSA-N Vitamin D2 Natural products C1CCC2(C)C(C(C)C=CC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C MECHNRXZTMCUDQ-UHFFFAOYSA-N 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 229940124532 absorption promoter Drugs 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
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 1
- 238000012387 aerosolization Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 206010002224 anaplastic astrocytoma Diseases 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 208000007474 aortic aneurysm Diseases 0.000 description 1
- 208000002399 aphthous stomatitis Diseases 0.000 description 1
- 208000021780 appendiceal neoplasm Diseases 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000007961 artificial flavoring substance Substances 0.000 description 1
- FIVPIPIDMRVLAY-UHFFFAOYSA-N aspergillin Natural products C1C2=CC=CC(O)C2N2C1(SS1)C(=O)N(C)C1(CO)C2=O FIVPIPIDMRVLAY-UHFFFAOYSA-N 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 235000013527 bean curd Nutrition 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 201000010295 benign neonatal seizures Diseases 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 150000003924 bisindolylmaleimides Chemical class 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 229940046731 calcineurin inhibitors Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229920003064 carboxyethyl cellulose Polymers 0.000 description 1
- 239000002340 cardiotoxin Substances 0.000 description 1
- 231100000677 cardiotoxin Toxicity 0.000 description 1
- 208000003295 carpal tunnel syndrome Diseases 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 238000010568 chiral column chromatography Methods 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 208000016532 chronic granulomatous disease Diseases 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000013507 chronic prostatitis Diseases 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 208000008609 collagenous colitis Diseases 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 239000008380 degradant Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 229960001378 dequalinium chloride Drugs 0.000 description 1
- LTNZEXKYNRNOGT-UHFFFAOYSA-N dequalinium chloride Chemical compound [Cl-].[Cl-].C1=CC=C2[N+](CCCCCCCCCC[N+]3=C4C=CC=CC4=C(N)C=C3C)=C(C)C=C(N)C2=C1 LTNZEXKYNRNOGT-UHFFFAOYSA-N 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 150000001982 diacylglycerols Chemical class 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 150000004659 dithiocarbamates Chemical class 0.000 description 1
- 201000008243 diversion colitis Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 229960002852 ellagic acid Drugs 0.000 description 1
- 235000004132 ellagic acid Nutrition 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 208000010227 enterocolitis Diseases 0.000 description 1
- 208000037828 epithelial carcinoma Diseases 0.000 description 1
- 229960002061 ergocalciferol Drugs 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 201000008819 extrahepatic bile duct carcinoma Diseases 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000020932 food allergy Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 201000010603 frozen shoulder Diseases 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 235000010492 gellan gum Nutrition 0.000 description 1
- 239000000216 gellan gum Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 208000028326 generalized seizure Diseases 0.000 description 1
- 201000007116 gestational trophoblastic neoplasm Diseases 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- FIVPIPIDMRVLAY-RBJBARPLSA-N gliotoxin Chemical compound C1C2=CC=C[C@H](O)[C@H]2N2[C@]1(SS1)C(=O)N(C)[C@@]1(CO)C2=O FIVPIPIDMRVLAY-RBJBARPLSA-N 0.000 description 1
- 229940103893 gliotoxin Drugs 0.000 description 1
- 229930190252 gliotoxin Natural products 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 229960002706 gusperimus Drugs 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 201000010235 heart cancer Diseases 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 208000024348 heart neoplasm Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- MPGWGYQTRSNGDD-UHFFFAOYSA-N hypericin Chemical compound OC1=CC(O)=C(C2=O)C3=C1C1C(O)=CC(=O)C(C4=O)=C1C1=C3C3=C2C(O)=CC(C)=C3C2=C1C4=C(O)C=C2C MPGWGYQTRSNGDD-UHFFFAOYSA-N 0.000 description 1
- PHOKTTKFQUYZPI-UHFFFAOYSA-N hypericin Natural products Cc1cc(O)c2c3C(=O)C(=Cc4c(O)c5c(O)cc(O)c6c7C(=O)C(=Cc8c(C)c1c2c(c78)c(c34)c56)O)O PHOKTTKFQUYZPI-UHFFFAOYSA-N 0.000 description 1
- 229940005608 hypericin Drugs 0.000 description 1
- 201000006866 hypopharynx cancer Diseases 0.000 description 1
- 208000034287 idiopathic generalized susceptibility to 7 epilepsy Diseases 0.000 description 1
- 208000009326 ileitis Diseases 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 231100000566 intoxication Toxicity 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 201000008222 ischemic colitis Diseases 0.000 description 1
- 201000002529 islet cell tumor Diseases 0.000 description 1
- 230000000155 isotopic effect Effects 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
- 208000022013 kidney Wilms tumor Diseases 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 201000006721 lip cancer Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 235000010420 locust bean gum Nutrition 0.000 description 1
- 239000000711 locust bean gum Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 208000020984 malignant renal pelvis neoplasm Diseases 0.000 description 1
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- VDXZNPDIRNWWCW-JFTDCZMZSA-N melittin Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(N)=O)CC1=CNC2=CC=CC=C12 VDXZNPDIRNWWCW-JFTDCZMZSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000006996 mental state Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- FAARLWTXUUQFSN-UHFFFAOYSA-N methylellagic acid Natural products O1C(=O)C2=CC(O)=C(O)C3=C2C2=C1C(OC)=C(O)C=C2C(=O)O3 FAARLWTXUUQFSN-UHFFFAOYSA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 239000003094 microcapsule Substances 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
- 230000006724 microglial activation Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 239000006082 mold release agent Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 210000000337 motor cortex Anatomy 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- IDINUJSAMVOPCM-INIZCTEOSA-N n-[(1s)-2-[4-(3-aminopropylamino)butylamino]-1-hydroxy-2-oxoethyl]-7-(diaminomethylideneamino)heptanamide Chemical compound NCCCNCCCCNC(=O)[C@H](O)NC(=O)CCCCCCN=C(N)N IDINUJSAMVOPCM-INIZCTEOSA-N 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000007472 neurodevelopment Effects 0.000 description 1
- 230000003962 neuroinflammatory response Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000000181 nicotinic agonist Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 210000000869 occipital lobe Anatomy 0.000 description 1
- 201000002575 ocular melanoma Diseases 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- GTVPOLSIJWJJNY-UHFFFAOYSA-N olomoucine Chemical compound N1=C(NCCO)N=C2N(C)C=NC2=C1NCC1=CC=CC=C1 GTVPOLSIJWJJNY-UHFFFAOYSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 201000006958 oropharynx cancer Diseases 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 208000021284 ovarian germ cell tumor Diseases 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 208000022102 pancreatic neuroendocrine neoplasm Diseases 0.000 description 1
- 208000003154 papilloma Diseases 0.000 description 1
- 208000029211 papillomatosis Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 201000007052 paranasal sinus cancer Diseases 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229960000292 pectin Drugs 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 1
- 239000002644 phorbol ester Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- MBWXNTAXLNYFJB-NKFFZRIASA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-NKFFZRIASA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- CDRPUGZCRXZLFL-OWOJBTEDSA-N piceatannol Chemical compound OC1=CC(O)=CC(\C=C\C=2C=C(O)C(O)=CC=2)=C1 CDRPUGZCRXZLFL-OWOJBTEDSA-N 0.000 description 1
- 208000020943 pineal parenchymal cell neoplasm Diseases 0.000 description 1
- 208000010916 pituitary tumor Diseases 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 229960003548 polymyxin b sulfate Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 235000012015 potatoes Nutrition 0.000 description 1
- 201000011461 pre-eclampsia Diseases 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 1
- 239000000770 propane-1,2-diol alginate Substances 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- SSKVDVBQSWQEGJ-UHFFFAOYSA-N pseudohypericin Natural products C12=C(O)C=C(O)C(C(C=3C(O)=CC(O)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 SSKVDVBQSWQEGJ-UHFFFAOYSA-N 0.000 description 1
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000007444 renal pelvis carcinoma Diseases 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000008458 response to injury Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 229960003471 retinol Drugs 0.000 description 1
- 235000020944 retinol Nutrition 0.000 description 1
- 239000011607 retinol Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 238000009490 roller compaction Methods 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 150000003902 salicylic acid esters Chemical class 0.000 description 1
- 201000003804 salivary gland carcinoma Diseases 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000003238 somatosensory effect Effects 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 208000037969 squamous neck cancer Diseases 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 201000008205 supratentorial primitive neuroectodermal tumor Diseases 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000003568 synaptosome Anatomy 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229960003454 tamoxifen citrate Drugs 0.000 description 1
- FQZYTYWMLGAPFJ-OQKDUQJOSA-N tamoxifen citrate Chemical compound [H+].[H+].[H+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 FQZYTYWMLGAPFJ-OQKDUQJOSA-N 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- 208000008732 thymoma Diseases 0.000 description 1
- 201000009377 thymus cancer Diseases 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 230000036977 tonic contraction Effects 0.000 description 1
- 208000028325 tonic-clonic seizure Diseases 0.000 description 1
- 239000008181 tonicity modifier Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 230000006439 vascular pathology Effects 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 235000010374 vitamin B1 Nutrition 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019164 vitamin B2 Nutrition 0.000 description 1
- 239000011716 vitamin B2 Substances 0.000 description 1
- 235000021470 vitamin B5 (pantothenic acid) Nutrition 0.000 description 1
- 235000019158 vitamin B6 Nutrition 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 235000021467 vitamin B7(Biotin) Nutrition 0.000 description 1
- 235000019159 vitamin B9 Nutrition 0.000 description 1
- 239000011727 vitamin B9 Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000001892 vitamin D2 Nutrition 0.000 description 1
- 239000011653 vitamin D2 Substances 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
- A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及3‑(1,2,3,6‑四氢吡啶‑2‑基)吡啶戊二酸盐或其药学上可接受的溶剂化物、其晶体和该晶体的多晶型物。本发明还涉及它们中的每一种的医学用途,特别是在物质成瘾或炎症的治疗或预防中的用途。
Description
本发明涉及3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐或其药学上可接受的溶剂化物、其晶体和该晶体的多晶型物。本发明还涉及它们中的每一种的医学用途,特别是在物质成瘾或炎症的治疗或预防中的用途。
背景技术
炎症是对有害刺激如氧化应激、刺激物、病原体和受损细胞的保护性反应。炎症反应涉及通过直接或间接地产生反应性氧物种和/或传导释放将产生反应性氧物种的试剂的信号来产生和释放将愈合受伤组织和破坏受损细胞的炎症调节剂。因此,适宜的炎症反应涉及受损细胞的破坏与受伤组织的愈合之间的平衡。
不受限制的炎症反应可能导致氧化应激和各种炎症性疾病病理的发作。实际上,炎症过程构成多种病理的起因,包括免疫和自身免疫疾病、胃肠道疾病、各种类型的癌症、血管病症、心脏疾病和神经退行性疾病。本领域需要可降低不适当的炎症水平的试剂。
发明内容
本发明涉及3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐(本文也称戊二酸新烟草碱)或其药学上可接受的溶剂化物、其晶体和该晶体的多晶型物。本发明还涉及它们中的每一种的医学用途,特别是在物质成瘾或炎症的治疗或预防中的用途。
可向个体施用包含治疗有效剂量的戊二酸新烟草碱、其药学上可接受的溶剂化物、其晶体和/或该晶体的多晶型物的药物组合物,以减轻包含NFKB-介导炎性成分的症状或病症和/或降低罹患这样的病症的风险。NFKB-介导炎性成分优选例如在甲状腺炎、癌症、关节炎、阿尔茨海默氏病和多发性硬化症中发生的慢性炎症。治疗有效剂量的戊二酸新烟草碱、其药学上可接受的溶剂化物、其晶体和/或该晶体的多晶型物也可以缓释制剂提供。在其他实施方案中,可在瓶装水产品中提供分离的形式的戊二酸新烟草碱、其药学上有效的溶剂化物、其晶体和/或其多晶型物,瓶装水产品包含例如约1ml至约2,000ml的纯净水和约0.00001至约0.0001重量%的戊二酸新烟草碱。所要求保护的化合物、晶体、多晶型物和/或药物组合物可具有单胺氧化酶(MAO)抑制作用。另外或替代地,本发明的化合物、晶体、多晶型物和/或药物组合物可具有STAT3磷酸化抑制作用。
特别地,本发明涉及以下实施方案:
1.一种化合物,所述化合物为3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐或其药学上可接受的溶剂化物。
2.根据实施方案1的化合物,其中所述3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐具有1:1的3-(1,2,3,6-四氢吡啶-2-基)吡啶与戊二酸盐的摩尔比。
3.根据实施方案1或2的化合物,其中所述3-[1,2,3,6-四氢吡啶-2-基]吡啶为3-[(2S)-1,2,3,6-四氢吡啶-2-基]吡啶。
4.根据实施方案1的化合物,其中所述3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐具有下式(I):
5.根据实施方案1至4中任一项的化合物,其中所述3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐具有下式(Ia):
6.根据实施方案1至5中任一项的化合物的晶体。
7.根据实施方案1至5中任一项的化合物或根据实施方案6的晶体的多晶型形式。
8.根据实施方案7的多晶型形式,其中所述多晶型形式具有大体上如图1所示的X-射线粉末衍射图谱(CuKα)。
9.根据实施方案7或8的多晶型形式,其中所述多晶型形式具有包括一个或多个选自8.0±0.2°2θ、11.0±0.2°2θ、13.3±0.2°2θ、16.5±0.2°2θ、18.0±0.2°2θ、20.7±0.2°2θ、21.0±0.2°2θ、21.4±0.2°2θ、22.0±0.2°2θ、22.3±0.2°2θ、23.3±0.2°2θ和24.5±0.2°2θ的峰的X-射线粉末衍射图谱(CuKα)。
10.根据实施方案1至5中任一项的化合物、根据实施方案6的晶体或根据实施方案7至9中任一项的多晶型形式作为药剂的用途。
11.根据实施方案1至5中任一项的化合物、根据实施方案6的晶体或根据实施方案7至9中任一项的多晶型形式在物质成瘾或炎症的治疗或预防中的用途。
12.一种用于治疗或预防物质成瘾或炎症的药物组合物,所述组合物包含药学有效量的根据实施方案1至5中任一项的化合物、根据实施方案6的晶体或根据实施方案7至9中任一项的多晶型形式中的一种或多种,任选地与一种或多种药学上可接受的赋形剂一起。
13.一种用于在有此需要的人或非人动物患者中治疗或预防物质成瘾或炎症的方法,其中所述方法包括向所述患者施用治疗有效量的根据实施方案1至5中任一项的化合物、根据实施方案6的晶体、根据实施方案7至9中任一项的多晶型形式或根据实施方案12的药物组合物中的至少之一。
14.一种用于制备根据实施方案1至5中任一项的化合物、根据实施方案6的晶体或根据实施方案7至9中任一项的多晶型形式的方法,所述方法包括步骤:
制备包含3-[1,2,3,6-四氢吡啶-2-基]吡啶、戊二酸和溶剂的溶液,
使得形成3-[1,2,3,6-四氢吡啶-2-基]吡啶与戊二酸的盐,以及
回收3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐。
15.根据实施方案14的方法,其中在3-[1,2,3,6-四氢吡啶-2-基]吡啶、戊二酸和溶剂的溶液的制备中使用的溶剂包括2-甲基四氢呋喃、乙腈和/或乙酸乙酯。
16.用于根据实施方案11的用途的根据实施方案1至5中任一项的化合物、根据实施方案6的晶体、根据实施方案7至9中任一项的多晶型形式,或者用于根据实施方案12的用途的药物组合物,其中所述物质选自尼古丁、可卡因、海洛因、大麻和酒精。
17.用于根据实施方案11的用途的根据实施方案1至5中任一项的化合物、根据实施方案6的晶体、根据实施方案7至9中任一项的多晶型形式,或者用于根据实施方案12的用途的药物组合物,其中所述炎症选自阿尔茨海默氏病、甲状腺炎和多发性硬化症。
18.用于根据实施方案11的用途的根据实施方案1至5中任一项的化合物、根据实施方案6的晶体、根据实施方案7至9中任一项的多晶型形式,或者用于根据实施方案12的用途的药物组合物,其在干粉吸入器中。
19.用于根据实施方案11的用途的根据实施方案1至5中任一项的化合物、根据实施方案6的晶体、根据实施方案7至9中任一项的多晶型形式,或者用于根据实施方案12的用途的药物组合物,其在热蒸发气溶胶装置中。
附图说明
图1:戊二酸新烟草碱的优选多晶型物的X-射线粉末衍射图谱(CuKα)
图2:实施例1中获得的戊二酸新烟草碱的1H NMR波谱
图3:正电离模式下戊二酸新烟草碱的总离子电流色谱图
图4:正电离模式下戊二酸新烟草碱的质谱图
图5:戊二酸新烟草碱的FTIR光谱
图6:新烟草碱游离碱的FTIR光谱
图7:戊二酸新烟草碱的X-射线衍射图,带峰位置
图8:戊二酸新烟草碱的TGA热谱图
图9:戊二酸新烟草碱的DSC热谱图
图10:戊二酸新烟草碱的DVS曲线图
图11:戊二酸新烟草碱的离子色谱图
图12:戊二酸新烟草碱的环境稳定性样品在T=0、3和7天时。
图13:酒石酸新烟草碱的XRPD衍射图谱
图14:柠檬酸新烟草碱的XRPD衍射图谱
具体实施方式
本发明涉及戊二酸新烟草碱来治疗包含炎性成分的病症,包括慢性、低水平的炎症。新烟草碱是一种生物碱,存在于烟草中,并以较低的浓度存在于各种食物中,包括青番茄、青土豆、成熟红胡椒、黏果酸浆和番茄干。如US 9,387,201和WO 2013/032558中所公开,它是提供抗炎支持的市售膳食补充剂Anatabloc的主要活性组分。分离的形式的新烟草碱的制备见述于WO 2011/119722中以及以下参考文献Ref-1至Ref-11中。
Ref-1:Rossi,F.V.;Ballini,R.;Barboni,L.;Allegrini,P.;Palmieri,A.Apractical and efficient synthesis of(±)-anatabine.Synthesis 2018,50(9),1921-1925。
Ref-2:Puthiaparampil,T.T.;David,T.K.;Raju,M.S.Methods of synthesizinganatabine.US Pat.8,207,346。
Ref-3:Puthiaparampil,T.T.;David,T.K.;Raju,M.S.Pharmaceutical,dietarysupplement,and food grade salts of anatabine.US Pat.8,557,999。
Ref-4:Saloranta,T.;Leino,R.From building block to natural products:ashort synthesis and complete NMR spectroscopic characterization of(±)-anatabine and(±)-anabasine.Tetrahedron Letters 2011,52(36),4619-4621。
Ref-5:Rouchaud,A.;Kem,W.R.A convenient racemic synthesis of twoisomeric tetrahydropyridyl alkaloids:isoanatabine and anatabine.Journal ofHeterocyclic Chemistry 2010,47(3),569-581。
Ref-6:yers,J.T.;Xu,R.;Dwoskin,L.P.;Crooks,P.A.A general procedure forthe enantioselective synthesis of the minor Tobacco alkaloids nornicotine,anabasine,and anatabine.The AAPS Journal 2005;7(3),Article 75。
Ref-7:Felpin,F.-X.;Vo-Thanh,G.;Robins,R.J.;Villieras,J.;Lebreton,J.Total synthesis of(S)-anabasine and(S)-anatabine.Synlett 2000,(11),1646-1648。
Ref-8:Yang,C.-M.;Tanner,D.D.A simple synthesis of(±)-1,2,3,6-tetrahydro-2,3'-bipyridine(anatabine)and(±)-3-(2-piperidinyl)pyridine(anabasine)from lithium aluminum hydride and pyridine.Canadian Journal ofChemistry 1997,75(6),616-620。
Ref-9:Deo,N.M.;Crooks,P.A.Regioselective alkylation of N-(diphenylmethylidine)-3-(aminomethyl)pyridine:a simple route to minor tobaccoalkaloids and related compounds.Tetr.Lett.1996,37(8),1137-1140。
Ref-10:Genisson,Y.;Mehmandoust,M.;Marazano,C.;Das,B.C.Chiral 1,2-dihydropyridines and 2,5-dihydropyridinium salt equivalents.Synthesis of(+)-anatabine and a chiral benzomorphane.Heterocycles 1994,39(2),811-818。
Ref-11:Quan,P.M.;Karns,T.K.B.;Quin,L.D.Total synthesis of dl-anatabine.Chemistry&Industry(London,United Kingdom)1964,(36),1553。
3-[1,2,3,6-四氢吡啶-2-基]吡啶(新烟草碱)以两种对映异构体存在,即R-(+)-新烟草碱和S-(-)-新烟草碱。新烟草碱的S-和R-对映异构体的对映选择性合成见述于例如Ayers,J.T.;Xu,R.;Dwoskin,L.P.;Crooks,P.A.A general procedure for theenantioselective synthesis of the minor Tobacco alkaloids nornicotine,anabasine,and anatabine.The AAPS Journal 2005;7(3)Article 75中。在本发明中,新烟草碱可以其两种对映异构体的外消旋混合物、以S-(-)-新烟草碱的纯化形式、或以R-(+)-新烟草碱的纯化形式使用。除非上下文另有明确说明,否则术语“新烟草碱”在本文中用来指(1)新烟草碱(R,S)的外消旋混合物、(2)S-(-)-新烟草碱的纯化形式、或(3)R-(+)-新烟草碱的纯化形式中的任何一种。
新烟草碱的药学上可接受的盐见述于美国专利8,207,346和美国专利8,557,999中。特别地,美国专利8,207,346的实施例6和美国专利8,557,999的实施例6描述了通过向新烟草碱在丙酮中的溶液中添加酒石酸或柠檬酸来制备酒石酸新烟草碱和柠檬酸新烟草碱。通过倾析、用乙醚研磨并在真空下干燥来分离形成的固体,但没有报道盐的收率。
戊二酸新烟草碱
在一个实施方案中,本发明涉及为3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐(本文也称戊二酸新烟草碱)的化合物或其药学上可接受的溶剂化物。3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐也可被称为3-(1,2,3,6-四氢吡啶-2-基)吡啶与戊二酸的盐。优选地,所述3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐具有1:1的3-(1,2,3,6-四氢吡啶-2-基)吡啶与戊二酸盐的摩尔比。
应理解,本文对“3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐”或“戊二酸新烟草碱”的任何提及应理解为也指其任何药学上可接受的溶剂化物。
更优选地,3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐具有由下式(I)表示的化学结构:
应指出,3-[1,2,3,6-四氢吡啶-2-基]吡啶(新烟草碱)以两种对映异构体存在,即R-(+)-新烟草碱和S-(-)-新烟草碱。在本发明中,3-[1,2,3,6-四氢吡啶-2-基]吡啶优选为3-[(2S)-1,2,3,6-四氢吡啶-2-基]吡啶。
在一个优选的实施方案中,3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐可因此具有下式(Ia):
本发明人已惊奇地发现,戊二酸新烟草碱以及在令人惊奇地改善的程度上晶体和晶体的多晶型物形式具有有利的性质如高结晶度、形态、对多晶型转化和/或脱水的热和力学稳定性、储存稳定性、低的残余溶剂含量、较低的吸湿性程度、可流动性以及有利的加工和操作特性。此外,本发明人发现,当通过合适的措施如真空下干燥来除去水分时,戊二酸新烟草碱即使在暴露于水分之后也会重结晶为结晶盐。这一发现非常出乎意料。
如从上文可见,新烟草碱以不同异构体的形式存在,特别是立体异构体(包括对映异构体和非对映异构体)或互变异构体。戊二酸新烟草碱的所有此类异构体都涵盖为是本发明的一部分,或以混合形式或以纯的或基本上纯的形式。至于立体异构体,本发明涵盖根据本发明的化合物的分离的光学异构体以及其任何混合物(特别是包括外消旋混合物/外消旋物)。外消旋物可通过物理方法拆分,如分步结晶、非对映异构体衍生物的分离或结晶、或通过手性柱色谱法的分离。各个光学异构体也可从外消旋物经由与光学活性酸形成盐然后结晶而获得。本发明还涵盖本文提供的化合物的任何互变异构体。
应理解,本文对3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐的任何提及也包括其任何溶剂化物和/或共晶体。溶剂化物包括任何类型的溶剂化物,包括例如与水的溶剂化物,例如水合物,或与有机溶剂如例如甲醇、乙醇或乙腈的溶剂化物,即分别为甲醇合物、乙醇合物或乙腈合物,或以任何多晶型物的形式。
本发明的范围还涵盖其中一个或多个原子被替换为相应原子的特定同位素的3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐。例如,本发明涵盖其中一个或多个氢原子(或例如所有氢原子)被替换为氘原子(即,2H;也称为“D”)的3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐。相应地,本发明还涵盖富含氘的3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐。天然存在的氢是同位素混合物,其包含约99.98摩尔%的氢-1(1H)和约0.0156摩尔%的氘(2H或D)。可使用本领域已知的氘代技术增加3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐中一个或多个氢位置处的氘含量。例如,可使用例如重水(D2O)对式(I)的化合物或待用于3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐的合成中的反应物或前体进行H/D交换反应。更多的合适的氘代技术见述于以下中:Atzrodt J et al.,Bioorg Med Chem,20(18),5658-5667,2012;William JS et al.,Journal of Labelled Compounds andRadiopharmaceuticals,53(11-12),635-644,2010;Modvig A et al.,J Org Chem,79,5861-5868,2014。氘的含量可例如使用质谱法或NMR波谱法测定。除非另有特别说明,否则优选3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐不富含氘。相应地,在3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐中存在天然存在的氢原子或1H氢原子是优选的。
用于选择性地制备新烟草碱对映异构体的方法见述于例如"A GeneralProcedure for the Enantioselective Synthesis of the Minor Tobacco AlkaloidsNornicotine,Anabasine,and Anatabine,"The AAPS Journal 2005;7(3)Article 75中。本文描述的任何方法或组合物可包括以其两种对映异构体的外消旋混合物、以S-(-)-新烟草碱的纯化形式、或以R-(+)-新烟草碱的纯化形式提供新烟草碱。除非上下文另有明确说明,否则术语“新烟草碱”在本文中用来指(1)新烟草碱(R,S)的外消旋混合物、(2)S-(-)-新烟草碱的纯化形式、或(3)R-(+)-新烟草碱的纯化形式中的任何一种。
本发明还涉及3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐的晶体。晶体不受特别限制并可具有任何形态。
本发明还涉及3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐的特定多晶型物(本文中也称多晶型形式),特别是3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐的晶体的特定多晶型物。多晶型物优选具有大体上如图1中所示的X-射线粉末衍射图谱(CuKα)。多晶型物优选具有包括一个或多个选自8.0±0.2°2θ、11.0±0.2°2θ、13.3±0.2°2θ、16.5±0.2°2θ、18.0±0.2°2θ、20.7±0.2°2θ、21.0±0.2°2θ、21.4±0.2°2θ、22.0±0.2°2θ、22.3±0.2°2θ、23.3±0.2°2θ和24.5±0.2°2θ的峰的X-射线粉末衍射图谱(CuKα)。更优选地,多晶型物优选具有包括一个或多个选自8.0±0.2°2θ、13.3±0.2°2θ、16.5±0.2°2θ、21.4±0.2°2θ、22.0±0.2°2θ和24.5±0.2°2θ的峰的X-射线粉末衍射图谱(CuKα)。
还更优选地,多晶型物优选具有包括一个或多个选自8.0±0.1°2θ、11.0±0.1°2θ、13.3±0.1°2θ、16.5±0.1°2θ、18.0±0.1°2θ、20.7±0.1°2θ、21.0±0.1°2θ、21.4±0.1°2θ、22.0±0.1°2θ、22.3±0.1°2θ、23.3±0.1°2θ和24.5±0.1°2θ的峰的X-射线粉末衍射图谱(CuKα)。甚至更优选地,多晶型物优选具有包括一个或多个选自8.0±0.1°2θ、13.3±0.1°2θ、16.5±0.1°2θ、21.4±0.1°2θ、22.0±0.1°2θ和24.5±0.1°2θ的峰的X-射线粉末衍射图谱(CuKα)。
甚至更特别地,多晶型物优选具有包括一个或多个选自7.960±0.2°2θ、10.907±0.2°2θ、13.291±0.2°2θ、14.413±0.2°2θ、15.239±0.2°2θ、16.479±0.2°2θ、17.933±0.2°2θ、20.610±0.2°2θ、20.977±0.2°2θ、21.318±0.2°2θ、21.927±0.2°2θ、22.203±0.2°2θ、22.792±0.2°2θ、23.246±0.2°2θ、24.426±0.2°2θ和24.769±0.2°2θ的峰的X-射线粉末衍射图谱(CuKα)。还更特别地,多晶型物优选具有包括一个或多个选自7.960±0.1°2θ、10.907±0.1°2θ、13.291±0.1°2θ、14.413±0.1°2θ、15.239±0.1°2θ、16.479±0.1°2θ、17.933±0.1°2θ、20.610±0.1°2θ、20.977±0.1°2θ、21.318±0.1°2θ、21.927±0.1°2θ、22.203±0.1°2θ、22.792±0.1°2θ、23.246±0.1°2θ、24.426±0.1°2θ和24.769±0.1°2θ的峰的X-射线粉末衍射图谱(CuKα)。
已使用离子色谱法分析来确认戊二酸盐以1:1的新烟草碱:戊二酸盐比率的存在。实验实例显示,戊二酸新烟草碱非常稳定,在加速条件(40℃/75%RH)下7天后未显示出降解的迹象。所提供的数据还显示,戊二酸新烟草碱可以单晶形式制备,所述单晶形式具有独特的晶体结构和物理性质,如熔点、X-射线衍射图谱、红外吸收指纹。
多晶型物筛选已导致没有新的戊二酸新烟草碱多晶型形式的产生。通过扫描电子显微镜及已在乙酸乙酯和乙腈中成熟的样品的DSC和XRPD图谱的比较进一步证实了这一点。通过热重分析(TGA)和差示扫描量热法(DSC)测定了戊二酸新烟草碱的热性质,其被用来区分晶体形式。
与戊二酸盐不同,酒石酸盐(图13)和柠檬酸盐(图14)具有非晶形式。柠檬酸盐和酒石酸盐是高度吸湿的,这使得其操作困难且具有挑战性,尤其是在大规模生产和配制中。此外,美国专利8,207,346和美国专利8,557,999中公开的柠檬酸盐的制备方法包括从丙酮中沉淀。因此,柠檬酸盐的固体形式含有截留的丙酮,如果不将固体转化为泡沫/胶,则其将难以除去。
本发明还涉及制备3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐的方法,特别是制备3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐的晶体的方法。
该方法包括步骤
a)制备包含3-[1,2,3,6-四氢吡啶-2-基]吡啶、戊二酸和溶剂的溶液,
b)使得形成3-[1,2,3,6-四氢吡啶-2-基]吡啶与戊二酸的盐,和
c)回收3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐。
在3-[1,2,3,6-四氢吡啶-2-基]吡啶、戊二酸和溶剂的溶液的制备中使用的溶剂优选包含2-甲基四氢呋喃、乙腈和/或乙酸乙酯。更优选地,溶剂包括2-甲基四氢呋喃。
所述方法可还包括步骤d)使3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐重结晶。用于该重结晶的合适溶剂包括乙腈。
在步骤a)中,可通过合并新烟草碱游离碱、溶剂和戊二酸以产生反应混合物来制备戊二酸新烟草碱。戊二酸新烟草碱通常在这样的反应混合物中通过新烟草碱游离碱与戊二酸的接触而形成。优选地,将新烟草碱游离碱以1至5质量%的乙腈溶液与戊二酸合并。
优选地,合并新烟草碱游离碱的溶液或悬浮液、溶剂和戊二酸以形成反应混合物,然后从该混合物沉淀并回收戊二酸新烟草碱。戊二酸可或以固体或以在溶剂中的溶液或悬浮液添加。
溶剂优选选自含1至8个碳原子的烷醇、含3至8个碳原子的脂族酯、含3至8个碳原子的脂族线形或环状醚、含3至8个碳原子的脂族酮、C6-12芳族烃(如苯和萘)、乙腈、水及其任何混合物。优选地,溶剂选自含3至8个碳原子的脂族酯、含3至8个碳原子的脂族环状醚、乙腈及其混合物。更优选地,溶剂选自乙酸乙酯、乙腈、2-甲基四氢呋喃及其任何混合物。甚至更优选地,溶剂含乙腈。还更优选地,溶剂为乙腈。
优选在约室温下(即,优选15℃至25℃的范围内)将新烟草碱游离碱、戊二酸和所述至少一种溶剂合并形成反应混合物。这样的反应混合物中存在的戊二酸的浓度优选为接近饱和点的浓度(例如,最大可实现浓度的至少80%、优选90%、更优选95%)。戊二酸新烟草碱通常会从混合物中沉淀出来。沉淀可自行发生或例如通过引入晶种而引起。可在沉淀之前、沉淀过程中或沉淀之后搅拌反应混合物。
可将反应混合物加热并然后冷却以促进戊二酸新烟草碱的沉淀。加热可在从室温到溶剂的沸腾温度的范围内的任何温度(例如,约50℃至约80℃)下进行。其后,通常进行冷却至低于40℃、优选约30℃至约20℃、更优选室温(即,优选15℃至25℃的范围)以促进沉淀。
所得沉淀物可通过各种技术如过滤来回收。沉淀物可在环境压力或减压和/或升高的温度下干燥。
医疗用途
根据本发明的方法可用的化合物具有穿过患者的血脑屏障的能力。因此,这样的化合物具有进入患者的中枢神经系统的能力。可用于实施本发明的典型化合物的log P值通常大于0,常大于约0.1,并经常大于约0.5。这样的典型化合物的log P值通常小于约3.0,常小于约2.5,并经常小于约2.0。Log P值提供了化合物穿过扩散屏障如生物膜的能力的量度。参见Hansch,et al.,J.Med.Chem.,Vol.11,p.1(1968)。
根据本发明的方法可用的化合物具有与患者的脑的烟碱胆碱能受体结合并因此引起其活化的能力。因此,这样的化合物具有充当烟碱激动剂的能力。可用于实施本发明的典型化合物的受体结合常数通常超过约1nM,常超过约200nM,并经常超过约500nM。这样的典型化合物的受体结合常数通常小于约10μM,常小于约7μM,并经常小于约2μM。受体结合常数提供了化合物结合患者某些脑细胞的一半相关受体位点的能力的量度。参见Cheng,etal.,Biochem.Pharmacol.,Vol.22,pp.3099-3108(1973)。
根据本发明的方法可用的化合物具有通过有效地引发神经末梢制剂(即,突触体)的神经递质分泌而显示出烟碱功能的能力。因此,这样的化合物具有使得相关神经元释放或分泌乙酰胆碱、多巴胺和其他神经递质的能力。通常,可用于实施本发明的典型化合物提供量为等摩尔量的(s)-(-)-尼古丁所引发的多巴胺的至少约3%、常至少约25%、经常至少约50%的多巴胺分泌。
因此,本发明涵盖本文所述的化合物、晶体或多晶型形式作为药剂的用途。所述药剂优选用在物质成瘾或炎症的治疗或预防中。在有此需要的人或非人动物患者中治疗或预防尼古丁成瘾或炎症的方法也是本发明的一部分。本发明还涉及用于治疗或预防物质成瘾或炎症的药物组合物,所述组合物包含药学有效量的本文所述化合物、晶体或多晶型形式中的一种或多种,任选地与一种或多种药学上可接受的赋形剂一起。
如本文所用,“人或非人动物患者”包括温血动物,通常为哺乳动物,包括人和其他灵长类动物。在一些实施方案中,患者为动物,如伴侣动物、服务动物、农场动物或动物园动物。这样的动物包括但不限于犬科动物(包括狗、狼)、猫科动物(包括家猫、老虎、狮子)、雪貂、兔、啮齿动物(例如,大鼠、小鼠)、豚鼠、仓鼠、沙鼠、马、奶牛、猪、绵羊、山羊、长颈鹿和大象。因此,如本文所公开的戊二酸新烟草碱既可用于人体治疗中又可用于兽医应用中。
在一些实施方案中,可施用分离的形式的戊二酸新烟草碱以降低罹患包含NFKB-介导炎性成分的病症的风险(即,预防性地)。人们可易于识别出罹患这样的病症的风险增加或有这样的病症的家族史的个体。可通过标准的临床试验或病史确定某些病症风险升高的其他公认指标。
在一些实施方案中,可施用分离的形式的戊二酸新烟草碱以降低罹患包含STAT3-介导炎性成分的病症的风险(即,预防性地)。人们可易于识别出罹患这样的病症的风险增加或有这样的病症的家族史的个体。可通过标准的临床试验或病史确定某些病症风险升高的其他公认指标。
炎症优选选自阿尔茨海默氏病、甲状腺炎和多发性硬化症。然而,可用所述化合物、晶体、多晶型形式或药物组合物治疗的病症的范围要广得多并将在下文中阐述:
-甲状腺炎,
-免疫或自身免疫病症,
-关节炎,如类风湿性关节炎、原发性和继发性骨关节炎(也称退行性关节疾病),
-脊椎关节病,如银屑病关节炎、伴血管翳迟发的青少年慢性关节炎和肠源性脊椎关节病如肠源性反应性关节炎、泌尿生殖器脊椎关节病和未分化的脊椎关节病,
-肌病,如“软组织风湿病”(例如,网球肘、冻结肩、腕管综合征、足底筋膜炎和跟腱炎),
-糖尿病,或I型糖尿病或II型糖尿病,
-胃肠道炎症性病症,如炎性肠病,例如,克罗恩氏病、巴瑞特综合征、回肠炎、肠易激综合征、结肠易激综合征、溃疡性结肠炎、假膜性结肠炎、出血性结肠炎、溶血性尿毒症综合征结肠炎、胶原性结肠炎、缺血性结肠炎、放射性结肠炎、药物和化学诱导的结肠炎、改道性结肠炎、慢性肉芽肿病等病中的结肠炎、乳糜泻病、乳糜性口炎性腹泻、食物过敏症、胃炎、感染性胃炎、小肠结肠炎(例如,幽门螺杆菌感染的慢性活动性胃炎)和结肠袋炎,
-移植物抗宿主病(GVHD)、系统性红斑狼疮(SLE)、狼疮性肾炎、爱迪生氏病、重症肌无力、血管炎(例如,韦格纳氏肉芽肿)、自身免疫性肝炎、骨质疏松症和一些类型的不育症,
-血管性炎症性疾病、相关的血管病理学、动脉粥样硬化、血管病、炎症引起的动脉粥样硬化或血栓栓塞性大血管病、冠状动脉疾病、脑血管疾病、外周血管疾病、心血管循环系统疾病如缺血/再灌注、外周血管疾病、血管成形术后再狭窄、炎症性主动脉瘤、血管炎、中风、脊髓损伤、充血性心力衰竭、失血性休克、缺血性心脏病/再灌注损伤、蛛网膜下腔出血后的血管痉挛、脑血管意外后的血管痉挛、胸膜炎、心包炎、炎症引起的心肌炎或糖尿病的心血管并发症,
-脑肿胀或神经退行性疾病如多发性硬化症、阿尔茨海默氏病或帕金森氏病。
-与肾病、肾炎、肾小球肾炎、透析、腹膜透析、心包炎、慢性前列腺炎、血管炎、痛风或胰腺炎有关的炎症,
-贫血症,
-与溃疡有关的疾病,如消化性溃疡病、急性胰腺炎或口疮性溃疡,
-与年龄有关的疾病,例如动脉粥样硬化、纤维化和骨质疏松症,或者与早熟相关的病症,如视网膜病变、慢性肺病、关节炎和消化问题,
-先兆子痫,与烧伤、酸和碱引起的化学或热创伤有关的炎症,化学中毒(MPTP/伴刀豆球蛋白/化学试剂/杀虫剂中毒),蛇、蜘蛛或其他昆虫咬伤,来自药物疗法的不良作用(包括来自两性霉素B治疗的不良作用),来自免疫抑制疗法(例如,白细胞介素-2治疗)的不良作用,来自OKT3治疗的不良作用,来自GM-CSF治疗的不良作用,环孢霉素治疗的不良作用和氨基糖苷治疗的不良作用,免疫抑制引起的口腔炎和粘膜炎,或电离辐射的暴露,如太阳紫外线暴露、核电厂或炸弹暴露、或放射疗法暴露(如用于癌症的疗法),
-癌症,如急性淋巴细胞白血病、急性髓细胞性白血病、肾上腺皮质癌、与艾滋病有关的淋巴瘤、肛门癌、阑尾癌、I级(间变性)星形细胞瘤、II级星形细胞瘤、III级星形细胞瘤、IV级星形细胞瘤、中枢神经系统的非典型畸胎瘤样/横纹肌样瘤、基底细胞癌、膀胱癌、乳腺癌、乳腺肉瘤、支气管癌、支气管肺泡癌、伯基特淋巴瘤、宫颈癌、慢性淋巴细胞性白血病、慢性粒细胞性白血病、结肠癌、结肠直肠癌、颅咽管瘤、皮肤T-细胞淋巴瘤、子宫内膜癌、子宫内膜子宫癌、成室管膜细胞瘤、室管膜瘤、食道癌、成感觉神经细胞瘤、尤因氏肉瘤、颅外生殖细胞瘤、性腺外生殖细胞瘤、肝外胆管癌、纤维组织细胞瘤、胆囊癌、胃癌、胃肠道类癌性肿瘤、胃肠道间质瘤、妊娠滋养细胞肿瘤、妊娠滋养细胞肿瘤、神经胶质瘤、毛细胞白血病、头颈癌、心脏癌、肝细胞癌、肝门胆管癌、霍奇金氏淋巴瘤、下咽癌、眼内黑色素瘤、胰岛细胞瘤、卡波西肉瘤、朗格汉斯细胞组织细胞增生症、大细胞未分化肺癌、喉癌、唇癌、肺腺癌、淋巴瘤、巨球蛋白血症、恶性纤维组织细胞瘤、髓母细胞瘤、髓上皮瘤、黑色素瘤、Merkel细胞癌、间皮瘤、内分泌腺肿瘤形成、多发性骨髓瘤、蕈样肉芽肿、脊髓发育不良、脊髓发育不良/骨髓增生性肿瘤、骨髓增生性病症、鼻腔癌、鼻咽癌、神经母细胞瘤、非霍奇金氏淋巴瘤、口腔癌、口咽癌、骨肉瘤、卵巢透明细胞癌、卵巢上皮癌、卵巢生殖细胞瘤、胰腺癌、多发性乳头瘤病、鼻旁窦癌、甲状旁腺癌、阴茎癌、咽癌、松果体实质肿瘤、成松果体细胞瘤、垂体瘤、浆细胞瘤、浆细胞瘤、胸膜肺母细胞瘤、原发性中枢神经系统淋巴瘤、前列腺癌、直肠癌、肾细胞癌、伴15号染色体改变的呼吸道癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、塞扎里综合征、小细胞肺癌、小肠癌、软组织肉瘤、鳞状细胞癌、鳞状非小细胞肺癌、鳞状颈癌、幕上原始神经外胚层肿瘤、幕上原始神经外胚层肿瘤、睾丸癌、喉癌、胸腺癌、胸腺瘤、甲状腺癌、肾盂癌、尿道癌、子宫肉瘤、阴道癌、外阴癌、瓦尔登斯特伦巨球蛋白血症或肾母细胞瘤,
-与胃和/或食道中的炎症相关的病症,如酸反流。
WO 2011/119722表明,新烟草碱将减少由核因子κΒ(NFKB)介导的转录。NFKB是一种在涉及炎症和免疫反应的细胞中起作用的转录因子。NFKB-介导的转录与许多病症相关,包括具有炎性成分、异常免疫应答和/或不适当的细胞增殖的病症。所要求保护的戊二酸新烟草碱特别适用于治疗包含“NFKB-介导炎性成分”的病症,即以NFKB-介导的转录为特征、由NFKB-介导的转录引起、由NFKB-介导的转录导致或受NFKB-介导的转录影响的炎症。NFKB-介导的转录牵涉在多种病痛中。基于戊二酸新烟草碱在干扰或中断这种关键的炎症相关活性方面令人惊奇的功效,可以预期戊二酸新烟草碱具有广泛的治疗效用。因此,预期本发明的化合物、晶体、多晶型形式和药物组合物可用在上文阐述的各种疾病的治疗或预防中。
本发明的化合物、晶体、多晶型形式和/或药物组合物也可与针对具有NFKB-介导成分的任何病症的其他疗法结合使用(即,在之前、之后或同时)。在一些实施方案中,这些疗法包括将抑制NFKB介导的炎性物质的产生的其他产品。这些产品包括但不限于地塞米松、糖皮质激素(例如,泼尼松、甲基泼尼松龙)、环孢霉素、他克莫司、脱氧精胍菌素、非类固醇类抗炎药(NSAID)如阿司匹林和其他水杨酸盐、替泊沙林、合成肽蛋白酶体抑制剂、抗氧化剂(例如,N-乙酰基-L-半胱氨酸、维生素C、维生素E、二硫代氨基甲酸酯衍生物、姜黄素)、IL-10、一氧化氮、cAMP、含金化合物和胶霉毒素。
本发明的化合物、晶体、多晶型形式和药物组合物可以足以减轻具有NFKB-介导转录成分的病症的症状的剂量施用于个体。
Paris et al.(2013)Europan Journal of Pharmacology 698,145-153也已证实,新烟草碱经由STAT3和NFkB信号传导的调节而在外周和CNS中均具有抗炎活性。相应地,除了NFKB外或替代地,本发明的化合物、晶体、多晶型物和/或药物组合物可抑制STAT3。所要求保护的戊二酸新烟草碱特别适用于治疗包含“STAT3-介导炎性成分”的病症,即以STAT3-介导的转录为特征、由其引起、由其导致或受其影响的炎症。STAT3-介导的转录牵涉在多种病痛中。基于戊二酸新烟草碱在干扰或中断这种关键的炎症相关活性方面令人惊奇的功效,可以预期戊二酸新烟草碱具有广泛的治疗效用。因此,预期本发明的化合物、晶体、多晶型形式和药物组合物可用在本文阐述的各种疾病的治疗或预防中。
本发明的化合物、晶体、多晶型形式和/或药物组合物也可与针对具有STAT3-介导成分的任何病症的其他疗法结合使用(即,在之前、之后或同时)。在一些实施方案中,这些疗法包括将抑制STAT3介导的炎性物质的产生的其他产品。在一个特别的实施方案中,本发明的化合物、晶体、多晶型物和/或药物组合物既具有STAT3抑制作用又具有NFKB抑制作用。
本发明的化合物、晶体、多晶型形式和药物组合物可以足以减轻具有STAT3-介导转录成分的病症的症状的剂量施用于个体。
在本发明的另一个实施方案中,可施用分离的形式的戊二酸新烟草碱来防止或治疗物质成瘾。可向患有物质成瘾的个体施用戊二酸新烟草碱以克服成瘾。可向已克服物质成瘾的个体施用戊二酸新烟草碱以防止其复发。还可向未患物质成瘾的个体施用戊二酸新烟草碱以防止其物质成瘾。物质成瘾的物质优选选自尼古丁、可卡因、海洛因、大麻和酒精。
WO 2012/2005885指出,含有新烟草碱的组合物对于暂时减少吸烟欲望、减少尼古丁渴望、戒烟的治疗、戒烟症状、烟草依赖、体重减轻和/或相关病症(甚至在不存在尼古丁的情况下)也是有效的。还已报道新烟草碱和其他次要生物碱会与烟碱受体结合。WO2015/009500进一步指出,新烟草碱可激活人烟碱乙酰胆碱受体,但可能需要超过任何推荐或耐受剂量的非常高的浓度来产生显著的激动剂效应。行为数据支持了这一建议,该数据表明,经训练自行施用尼古丁的啮齿动物未发现新烟草碱是有益的,并且新烟草碱施用没有逆转催促的尼古丁戒断。本发明基于的是戊二酸新烟草碱在这方面特别有效的这一令人惊奇的发现。此外,如本文所提供的特定结晶/多晶型形式是特别有效的。
在又一个实施方案中,本发明提供了一种治疗某些医学、精神病学和/或神经病学状况或病症的方法。在本发明的一个实施方案中,所述方法包括向哺乳动物、特别是人施用MAO抑制有效量的本发明的化合物、晶体、多晶型物和/或药物组合物以治疗医学、精神病学和/或神经病学状况和病症如但不限于阿尔茨海默氏病、帕金森氏病、重度抑郁症、轻度抑郁症、非典型性抑郁症、心境恶劣、注意力缺陷障碍、多动症、品行障碍、发作性睡病、社交恐惧症、强迫症、非典型性面部疼痛、进食障碍、药物戒断综合征和药物依赖性病症(包括对酒精、阿片类药物、安非他明、可卡因、烟草和大麻制品(大麻)的依赖性)、忧郁症、恐慌症、贪食症、缺乏活力性抑郁症、抗治疗性抑郁症、头痛、慢性疼痛综合征、普遍性焦虑障碍以及其中MAO活性的改变可能具有治疗价值的其他状况。
在本发明的又一个实施方案中,所述方法包括向哺乳动物、特别是人施用MAO抑制有效量的本发明的化合物、晶体、多晶型物和/或药物组合物以治疗医学、精神病学和/或神经病学状况和病症如但不限于阿尔茨海默氏病、帕金森氏病、重度抑郁症、轻度抑郁症、非典型性抑郁症、心境恶劣、注意力缺陷障碍、多动症、品行障碍、发作性睡病、社交恐惧症、强迫症、非典型性面部疼痛、进食障碍、药物戒断综合征和药物依赖性病症(包括对酒精、阿片类药物、安非他明、可卡因、烟草和大麻制品(大麻)的依赖性)、忧郁症、恐慌症、贪食症、缺乏活力性抑郁症、抗治疗性抑郁症、头痛、慢性疼痛综合征、普遍性焦虑障碍以及其中MAO活性的改变可能具有治疗价值的其他状况。
在本发明的又一个实施方案中,所述方法包括向哺乳动物、特别是人施用MAO抑制有效量的本发明的化合物、晶体、多晶型物和/或药物组合物以治疗医学、精神病学和/或神经病学状况和病症如但不限于阿尔茨海默氏病、帕金森氏病、重度抑郁症、轻度抑郁症、非典型性抑郁症、心境恶劣、注意力缺陷障碍、多动症、品行障碍、发作性睡病、社交恐惧症、强迫症、非典型性面部疼痛、进食障碍、药物戒断综合征和药物依赖性病症(包括对酒精、阿片类药物、安非他明、可卡因、烟草和大麻制品(大麻)的依赖性)、忧郁症、恐慌症、贪食症、缺乏活力性抑郁症、抗治疗性抑郁症、头痛、慢性疼痛综合征、普遍性焦虑障碍以及其中MAO活性的改变可能具有治疗价值的其他状况。
在本发明的又一个实施方案中,所述方法包括向哺乳动物、特别是人施用MAO抑制有效量的用本发明的化合物、晶体、多晶型物和/或药物组合物配制的呈口香糖和锭剂形式的本发明的化合物、晶体、多晶型物和/或药物组合物以治疗医学、精神病学和/或神经病学状况和病症如但不限于阿尔茨海默氏病、帕金森氏病、重度抑郁症、轻度抑郁症、非典型性抑郁症、心境恶劣、注意力缺陷障碍、多动症、品行障碍、发作性睡病、社交恐惧症、强迫症、非典型性面部疼痛、进食障碍、药物戒断综合征和药物依赖性病症(包括对酒精、阿片类药物、安非他明、可卡因、烟草和大麻制品(大麻)的依赖性)、忧郁症、恐慌症、贪食症、缺乏活力性抑郁症、抗治疗性抑郁症、头痛、慢性疼痛综合征、普遍性焦虑障碍以及其中MAO活性的改变可能具有治疗价值的其他状况。
在还又一个实施方案中,可施用本发明的化合物、晶体、多晶型物和/或药物组合物以治疗/预防自闭症谱系障碍(ASD)组的障碍或疾病。自闭症谱系障碍(ASD)是在幼儿期诊断出的广泛性神经发育障碍:获得性技能丧失或新技能的获得被延迟。ASD开始于幼儿期,除了重复性和刻板行为外,还伴随不同程度的沟通和社交技能障碍。在许多情况下(25%-50%),随着获得性技能的丧失或新技能的获得被延迟,看似正常发展的时期会急剧转变方向。自闭症谱系障碍的实例包括“经典”自闭症、阿斯伯格综合征、Rett综合征、童年瓦解性障碍和另外称为待分类的广泛性发展障碍(PDD-NOS)的非典型自闭症。
自闭症是一种儿童期精神病,起源于婴儿期,特征在于随着年龄的增长而出现广泛的心理症状(例如,在社交关系中缺乏响应性、语言异常以及对持续不断的环境输入的需要)。它通常出现在两到三岁的儿童中并导致儿童先前获得的发展的丧失。自闭症个体罹患癫痫发作病症如癫痫病的风险会增高。
在自闭症患者的结肠、食道和十二指肠中已发现过度的炎症,并且尸检研究也显示神经炎症的几种标记物的表达增加(参见表1)。在一些自闭症患者中,促炎性细胞因子(包括TNFα和IL-1)过度产生,表明这些患者具有过度的固有免疫应答和/或异常地产生针对T细胞应答的调节性细胞因子(例如,20030148955。分离的形式的新烟草碱,包括S-(-)-新烟草碱或这样的分离的形式的盐,特别适用于治疗包含"NFκB-介导炎性成分"的病症,即以NFκB-介导的转录为特征、由NFκB-介导的转录引起、由NFκB-介导的转录导致或受NFκB-介导的转录影响的炎症。因此,呈分离的形式的式I化合物(例如,新烟草碱或S-(-)-新烟草碱或其药学上可接受的盐)可用于治疗或减轻ASD的症状。本发明的化合物、晶体、多晶型物和/或药物组合物的使用将避免与烟草、烟草提取物、生物碱提取物和尼古丁相关的毒性。
神经炎症是对中枢神经系统损伤的公认反应(Minghetti,Curr Opin Neurol2005;18:315-21)。阿尔茨海默氏病的人体病理学、体外和体内研究均已表明神经胶质介导的神经炎症反应涉及在该病的病理生理学中(Mrak&Griffin,Neurobiol Aging 26:349-54,2005)并作为治疗靶标(Hu et al.,Bioorgan Med Chem Lett 17:414-18,2007;Ralayet al,,J Neurosci 26:662-70,2006;Crafl et al.,Exp Opin Therap Targets 9:887-900,2005)。已提出导致IL-1的过表达的小胶质细胞激活是启动自传播细胞因子周期的关键性步骤,其最终导致神经变性(Mrak&Griffin,Neurobiol Aging 26:349-54,2005;Shengel al.,Neurobiol Aging 17:761-66.1996)。IL-1β和促炎性细胞因子可独立于这样的周期在癫痫病中充当促惊厥信号传导分子(Vezzani et al.,Epilepsia 43:S30-S35,2002),其提供了癫痫病和其他癫痫发作病症的潜在治疗靶标(Vezzani&Granata,Epilepsia 46:1724-43,2005)。
在一些实施方案中,施用分离的形式的本发明化合物、晶体、多晶型物和/或药物组合物来治疗癫痫发作,包括全身性和部分性癫痫发作。
如The Pharmacological Basis of Therapeutics,9th ed.,(McGraw-Hill)中所述,存在两类癫痫发作:部分性癫痫发作和全身性癫痫发作。部分性癫痫发作包括局灶性和局部性癫痫发作。部分性癫痫发作进一步分类为简单性部分性癫痫发作、复杂性部分性癫痫发作和部分性癫痫发作继发全面性强直阵挛。全身性癫痫发作分类为惊厥性和非惊厥性癫痫发作。它们进一步分类为失神(先前称为癫痫小发作)癫痫发作、非典型失神癫痫发作、肌阵挛癫痫发作、阵挛癫痫发作、强直癫痫发作、强直-阵挛癫痫发作和失张力癫痫发作。
全身性癫痫发作包括婴儿痉挛、失神癫痫发作、强直-阵挛癫痫发作、失张力癫痫发作和肌阵挛癫痫发作。运动功能异常和意识丧失是这些癫痫发作的主要特征。患者还可能经历感官感觉、自主神经感觉或精神感觉的先兆。先兆可包括感觉异常、上腹感觉上升、异常气味、恐惧感觉或似曾相识感觉。全身性癫痫发作后通常跟着癫痫发作后状态,在此状态下,患者可能深度入睡、感到困惑和/或头痛或肌肉疼痛。癫痫发作后状态中可能存在Todd麻痹(致痫灶对侧肢无力)。
婴儿痉挛的特征在于手臂的频繁弯曲和内收及躯干的前曲,通常持续时间较短。它们仅发生在生命的头5年。
典型的失神癫痫发作(也称癫痫小发作)的特征在于随着眼睑颤动而意识丧失,通常持续10-30秒或更长时间。轴向肌肉张力可能丧失或可能不丧失。没有抽搐;取而代之的是,患者突然停止活动,然后突然恢复活动,常常意识不到已发生癫痫发作。失神癫痫发作是遗传性的。它们主要发生在儿童身上,通常全天频繁发生。
非典型性失神发作作为Lennox-Gastaut综合征的一部分发生,该综合征是一种严重的癫痫病形式。它们比典型的失神癫痫发作持续更长时间,并且颤动或自动运动更为明显。
失张力癫痫发作最常在儿童中发生,通常作为Lennox-Gastaut综合征的一部分。它们的特征在于肌肉张力和意识的完全丧失。
强直癫痫发作也最常在儿童中发生,通常作为Lennox-Gastaut综合征的一部分。它们的特征在于轴向和近端肌肉的强直性(持续)收缩,通常在睡眠期间,并持续10至15秒。在较长时间的强直癫痫发作中,可能在癫痫发作结束时发生快速阵挛颤动。
强直-阵挛癫痫发作,也称癫痫大发作,可以是原发性或继发性全身性的。经历原发性全身性强直-阵挛癫痫发作的患者常会大哭,然后失去意识并跌倒。然后开始强直性收缩,接着是手脚、躯干和头部肌肉的阵挛(快速交替的收缩和松弛)运动。患者可能尿失禁和大便失禁,咬住舌头,并且口吐白沫。癫痫发作通常持续1至2分钟。没有先兆。继发性全身性强直-阵挛癫痫发作始于简单性部分性或复杂性部分性癫痫发作,然后进展为全身性癫痫发作。
肌阵挛癫痫发作的特征在于一肢、几肢或躯干的短暂、快速颤动。它们可能是重复性的,从而导致强直-阵挛癫痫发作。颤动可以是双侧的或单侧的。除非癫痫发作进展为全身性强直-阵挛癫痫发作,否则意识不会丧失。
青少年肌阵挛癫痫是一种以肌阵挛、强直-阵挛和失神癫痫发作为特征的癫痫综合征。患者通常为青少年。癫痫发作通常始于双侧同步肌阵挛颤动,随后90%进展成全身性强直-阵挛癫痫发作。它们通常在早晨起床时发生。三分之一的患者可能经历失神癫痫发作。
发热性癫痫发作与发烧相关,但与颅内感染无关。良性发热性癫痫发作以持续时间短暂的全身性强直-阵挛癫痫发作为特征。这样的癫痫发作在儿童中很常见,影响到六岁以下儿童中的百分之四。复杂性发热性癫痫发作以局灶性癫痫发作持续超过十五分钟或在二十四小时内发生不止两次为特征。百分之二的发热性癫痫发作儿童会罹患后续的癫痫发作病症。在患复杂性发热性癫痫发作、先前存在神经系统异常、在1岁之前发作或有癫痫发作病症家族史的儿童中,风险将更大。
癫痫持续状态是一种癫痫发作病症,特征在于强直-阵挛癫痫发作活动持续超过五至十分钟,或患者在两次或更多次癫痫发作之间未完全恢复意识。如果不治疗,持续超过六十分钟的癫痫发作可能导致脑损伤或死亡。
复杂性部分性癫痫持续状态和失神癫痫持续状态以长时间的精神状态改变为特征。全身惊厥性癫痫持续状态可能与突然停用抗惊厥药或头部创伤相关。
简单性部分性癫痫发作以运动、感觉或精神运动症状为特征而无意识丧失。脑的不同部位的癫痫发作常产生截然不同的症状。
复杂性部分性癫痫发作之前常有先兆。患者通常知道自己的环境,但可能会意识受损。患者还可能出现口腔自动症(无意识地咀嚼或咂嘴)、手或肢自动症(无目的的自动运动)、发声不清、致痫灶对侧手脚的强直性或张力障碍性姿势、头眼歪斜(通常在致痫灶对侧的方向上)和腿的骑行或踩踏运动,尤其是在癫痫发作源自于内侧额叶或眶额叶区的情况下。运动症状在一或两分钟后消退,并在一至两分钟后出现困惑和方向障碍,常见发作后遗忘症。
癫痫病是癫痫发作病症的一个重要实例。“癫痫病”描述了一组中枢神经系统疾病,其以反复的癫痫发作为特征,该反复的癫痫发作是大脑皮层和脑的其他区域的神经元过度和/或超同步异常电活动的外在表现。这种异常的电活动可表现为运动、抽搐、感觉、自主神经或精神症状。
数百种癫痫综合征已被定义为以包括癫痫发作在内的特定症状为特征的病症。这些病症包括但不限于失神癫痫、精神运动性癫痫、颞叶癫痫、额叶癫痫、枕叶癫痫、顶叶癫痫、Lennox-Gastaut综合征、拉斯穆森氏脑炎、儿童失神癫痫、Ramsay Hunt II型综合征、良性癫痫综合征、良性婴儿脑病、良性新生儿惊厥、早期肌阵挛性脑病、进行性癫痫和婴儿癫痫。患者可能患有不同类型癫痫发作的任何组合。部分性癫痫发作是最常见的,并占所有癫痫发作类型的大约60%。
可以治疗的全身性癫痫发作的实例包括婴儿痉挛、典型性失神癫痫发作、非典型失神癫痫发作、失张力癫痫发作、强直癫痫发作、强直-阵挛癫痫发作、肌阵挛癫痫发作和发热性癫痫发作。可以治疗的部分性癫痫发作的实例包括影响额叶、对侧额叶、补充性运动皮层、脑岛、脑岛-眶-额叶皮层、前内侧颞叶、杏仁核(包括岛盖和/或其他区域)、颞叶、后颞叶、杏仁核、海马体、顶叶(包括感觉皮层和/或其他区域)、枕叶和/或脑的其他区域的简单性部分性癫痫发作。
在一些实施方案中,施用分离的形式的本发明化合物、晶体、多晶型物和/或药物组合物以治疗癫痫综合征,包括但不限于失神癫痫、精神运动性癫痫、颞叶癫痫、额叶癫痫、枕叶癫痫、顶叶癫痫、Lennox-Gastaut综合征、拉斯穆森氏脑炎、儿童失神癫痫、RamsayHunt II型综合征、良性癫痫综合征、良性婴儿脑病、良性新生儿惊厥、早期肌阵挛性脑病、进行性癫痫和婴儿癫痫。
分离的形式的本发明化合物、晶体、多晶型物和/或药物组合物也可用于治疗伴随癫痫发作的先兆。因此,也可治疗意识障碍、口部自动症、手或肢自动症、发声不清、手脚的强直性或张力障碍性姿势、头眼歪斜、腿的骑行或踩踏运动及包含先兆的其他症状。
新生儿癫痫发作与后来的神经发育和认知缺陷相关,包括智力迟钝、自闭症和癫痫病,并据估计,高达40%的自闭症病例患有癫痫病或在生命早期具有癫痫发作史。因此,重要的目标患者是婴儿,特别是新生儿,以及个人或家族有癫痫发作、智力迟钝或自闭症史的人。
本公开还提供了用于治疗癫痫发作后的患者的方法和组合物。在一个实施方案中,将分离的形式的本发明化合物、晶体、多晶型物和/或药物组合物与第二治疗剂联合施用,所述第二治疗剂为如神经递质受体抑制剂(AMPA受体、NMDA受体、GABA受体、氯共转运体或代谢型谷氨酸受体的抑制剂)、激酶/磷酸酶抑制剂(例如,钙调蛋白激酶II(CamK II)、蛋白激酶A(PKA)、蛋白激酶C(PKC)、MAP激酶、Src激酶、ERK激酶或磷酸酶钙调神经磷酸酶的抑制剂)和/或蛋白质翻译抑制剂。
钙调蛋白激酶II(CamK II)抑制剂包括KN-62、W-7、HA-1004、HA-1077和十字孢碱。蛋白激酶A(PKA)抑制剂包括H-89、HA-1004、H-7、H-8、HA-100、PKI和十字孢碱。
蛋白激酶C(PKC)抑制剂包括针对PKC ATP-结合位点的竞争性抑制剂,包括十字孢碱及其双吲哚基马来酰亚胺衍生物Ro-31-7549、Ro-31-8220、Ro-31-8425、Ro-32-0432和桑霉素;通过在二酰基甘油和佛波酯的结合位点竞争而与PKC的调节结构域相互作用的药物,如钙磷酸蛋白C、沙芬戈、D-赤型-鞘氨醇;靶向PKC的催化结构域的药物,如氯化白屈菜红碱和蜂毒肽;通过在UV光暴露下与PKC共价结合而抑制PKC的药物,如地喹氯铵;特异性抑制Ca-依赖性PKC的药物,如Go6976、Go6983、Go7874和其他同系物、多粘菌素B硫酸盐;包含源自PKC序列的竞争性肽的药物;和[0056]PKC抑制剂,如心脏毒素、鞣花酸、HBDDE、1-O-十六烷基1-2-O-甲基-rac-甘油、金丝桃素、K-252、NGIC-1、根皮素、白皮杉醇和柠檬酸他莫昔芬。
MAP激酶抑制剂包括SB202190和SB203580。SRC激酶抑制剂包括PP1、PP2、5号Src抑制剂、SU6656和十字孢碱。ERK激酶抑制剂包括PD 98059、SL327、奥罗莫星和5-碘代杀结核菌素。钙调神经磷酸酶抑制剂包括他克莫司和环孢霉素。
蛋白质翻译抑制剂包括mTOR抑制剂,如雷帕霉素、CCI-779和RAD 001。
将分离的形式的本发明化合物、晶体、多晶型物和/或药物组合物以足以减轻自闭症谱系障碍的症状的剂量或足以减轻癫痫发作病症的症状的剂量施用于个体。剂量通常在约1μg/kg至约7mg/kg体重(例如,约1、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9或5μg/kg或约0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2、2,1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9或5mg/kg)、约1.5μg/kg至约5μg/kg、约1μg/kg至约10μg/kg、约0.01mg/kg至约7mg/kg体重、约0.1mg/kg至约5mg/kg、约0.1mg/kg至约2mg/kg、约1mg/kg至约3mg/kg、约0.5mg/kg至约2mg/kg、约1mg/kg至约2mg/kg、约3mg/kg至约5mg/kg、约2mg/kg至约4mg/kg、约2mg/kg至约5mg/kg、或约0.5mg/kg至约1.5mg/kg的范围内。某些因素可能影响足以减轻病症症状的剂量(即,有效剂量),包括疾病或病症的严重性、先前的治疗、个体的总体健康状况、年龄和/或重量、治疗的频率、从组合物释放的速率和存在的其他疾病。该剂量可随因素如受试者的疾病状态、年龄和体重而异。例如,对于处于晚期和/或危及生命的疾病的治疗,可施用较高的剂量。也可调整剂量方案以提供最佳治疗反应。
在一些实施方案中,足以减轻病症症状的剂量可包括一系列治疗。例如,可每天数次(例如,每天2-12次或4-10次)、每天一次或更低的频率如每周1-6次用一定剂量的分离的形式的本发明化合物、晶体、多晶型物和/或药物组合物来治疗个体。在其他实施方案中,施用的化合物为式I、IA或IB的化合物,其每天施用数次(例如,每天2-12次或4-10次)、每天一次或更低频率如每周1-6次。治疗时间跨度可为约1至10周之间(例如,2至8周之间、3至7周之间、约1、2、3、4、5、6、7、8、9或10周)。还应理解,用于治疗的剂量方案可在特定治疗的过程中增加或减少。
在本发明的一个实施方案中,向患者施用戊二酸新烟草碱以治疗或预防物质成瘾或炎症。剂量通常在约1μg/kg至约7mg/kg体重(例如,约1、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9或5μg/kg或约0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2、2,1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9或5mg/kg)、约1.5μg/kg至约5μg/kg、约1μg/kg至约10μg/kg、约0.01mg/kg至约7mg/kg体重、约0.1mg/kg至约5mg/kg、约0.1mg/kg至约2mg/kg、约1mg/kg至约3mg/kg、约0.5mg/kg至约2mg/kg、约1mg/kg至约2mg/kg、约3mg/kg至约5mg/kg、约2mg/kg至约4mg/kg、约2mg/kg至约5mg/kg、或约0.5mg/kg至约1.5mg/kg的范围内。某些因素可能影响足以减轻病症症状的剂量(即,有效剂量),包括疾病或病症的严重性、先前的治疗、个体的总体健康状况、年龄和/或重量、治疗的频率、从组合物释放的速率和存在的其他疾病。该剂量可随因素如受试者的疾病状态、年龄和体重而异。例如,对于处于晚期和/或危及生命的疾病的治疗,可施用较高的剂量。也可调整剂量方案以提供最佳治疗反应。
例如,包含约600μg戊二酸新烟草碱的片剂每天施用一次至25次(例如,每天施用1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25次)。
足以减轻病症症状的剂量可任选地包括一系列治疗。例如,可每天数次、每天一次、或更低频率如每周1-6次用一定剂量的分离的形式的戊二酸新烟草碱治疗个体。炎症的治疗时间跨度可为约1至10周之间(例如,2至8周之间、3至7周之间、约1、2、3、4、5、6、7、8、9或10周)。施用戊二酸新烟草碱以预防炎症可进行无限长的时间跨度并可相应地调整剂量。戊二酸新烟草碱可根据满足渴望的需要施用无限长的时间跨度以预防和治疗物质成瘾,或每隔一定时间施用,如每天一次、每天两次或每天三次或更多次,具体取决于因素如戊二酸新烟草碱的量和受试者的生理状况。还应理解,用于治疗的剂量方案可在特定治疗的过程中增加或减少。
通常,本发明中使用的戊二酸新烟草碱的纯度水平为至少约95%,更通常至少约96%、约97%、约98%或更高。例如,纯度水平可为约98.5%、99.0%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%、99.9%或更高。
戊二酸新烟草碱可与其他成分一起提供,例如,以酏剂、溶剂化物、饮料、含片、片剂、锭剂、口香糖等的形式。在一个实施方案中,例如,饮料可呈瓶装水产品的形式,所述瓶装水产品含约100ml至约2,000ml的纯净水和约0.00001至约0.0001重量%的戊二酸新烟草碱水溶性盐。可添加另外的非活性成分以改善产品特性,如味道、颜色/澄清度和/或稳定性。瓶装水产品还可含有其他有益组分,如维生素、蛋白质成分等。组合物可另外以固体(例如,粉末)形式提供,如在包装中提供,其可与水或其他液体合并(例如,由最终用户)来制备饮料。
包含本发明的化合物、晶体或多晶型形式的药物组合物可与一种或多种药学上可接受的赋形剂一起配制。如本文所用,术语“药学上可接受的赋形剂”指的是无毒、惰性的固体、半固体或液体填充剂、稀释剂、包囊材料或任何类型的制剂助剂。例如,根据配方师的判断,组合物中也可存在糖如乳糖、葡萄糖和蔗糖;淀粉如玉米淀粉和马铃薯淀粉;纤维素及其衍生物如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;西黄蓍胶粉;麦芽;明胶;滑石;赋形剂如可可脂和栓剂用蜡;油如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇如丙二醇;酯如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂如氢氧化镁和氢氧化铝;海藻酸;无热原水;等渗盐水;林格溶液;乙醇和磷酸盐缓冲溶液;相容的润滑剂如月桂基硫酸钠和硬脂酸镁;以及着色剂、脱模剂、包衣剂、甜味剂、调味剂和增香剂、防腐剂和抗氧化剂。
用于经口施用的液体剂型包括可接受的药物或食品级乳剂、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除了活性化合物外,液体剂型可还含有本领域常用的惰性稀释剂,如例如水或其他溶剂、增溶剂和乳化剂,如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基亚砜(DMSO)、二甲基甲酰胺、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和失水山梨糖醇的脂肪酸酯及其混合物。除了惰性稀释剂外,口服组合物还可包含佐剂,如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和增香剂。
用于热蒸发气溶胶装置中的液体药物组合物通常含有其他组分如水、有机溶剂、甜味剂和/或调味剂等。在用于热蒸发气溶胶装置的液体组合物中常用的溶剂的实例包括多元醇如1,2-丙二醇(PG或MPG);一元醇如乙醇;乙酸乙酯;等。存在的水的量通常在约0.1重量%至约10重量%、常常约0.5重量%至约5重量%的范围内。存在的有机溶剂的量通常在约50重量%至约99重量%、常约75重量%至约95重量%的范围内。如果需要,可向组合物中加入一种或多种调味剂,其非限制性实例包括胡椒薄荷、薄荷醇、冬青、留兰香、蜂胶、桉、肉桂等。基于组合物的总重量计,调味剂的总量通常在约0.5重量%至约15重量%、常约1重量%至约10重量%的范围内。举例来说,戊二酸新烟草碱的量可在每总的一克组合物约0.1至约25mg、约0.5至约20mg、或约1至约10mg的范围内。
用于经口施用的固体剂型包括胶囊剂、片剂、锭剂、丸剂、散剂和颗粒剂。在这样的固体剂型中,将活性化合物与至少一种惰性的、可接受的药物或食品级赋形剂或载体如柠檬酸钠或磷酸二钙和/或以下混合:a)填充剂或增量剂如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸,b)粘结剂如羧甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶,c)湿润剂如甘油,d)崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠,e)溶液阻滞剂如石蜡,f)吸收促进剂如季铵化合物,g)润湿剂如鲸蜡醇和单硬脂酸甘油酯,h)吸收剂如高岭土和膨润土,i)润滑剂如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物,和j)甜味剂、调味剂、增香剂及其混合物。对于胶囊剂、锭剂、片剂和丸剂,剂型还可包含缓冲剂。本发明的固体剂型可配制为缓慢释放的。
为了延长本发明的化合物、晶体、多晶型物和/或药物组合物的作用,常希望减慢来自皮下或肌内注射的物质的吸收。这可通过使用水溶性较差的结晶或非晶材料的液体悬浮体来实现。然后,物质的吸收速率取决于其溶解速率,溶解速率又可能取决于晶体大小和结晶形式。或者,通过将物质溶解或悬浮在油媒介物中来实现肠胃外施用的物质形式的延迟吸收。通过在可生物降解聚合物如聚丙交酯-聚乙交酯中形成物质的微胶囊基质来制备可注射储库形式。取决于物质与聚合物的比率和所采用的特定聚合物的性质,可控制物质释放的速率。其他可生物降解聚合物的实例包括聚(原酸酯)和聚(酸酐)。延长释放制剂是本领域已知的。例如,可溶胀颗粒在美国专利号5,582,837、5,972,389和6,723,340中有教导。聚合物基质在美国专利号6,210,710、6,217,903和6,090,411中有教导。用于延长释放制剂的典型材料有聚合物聚(环氧乙烷)和羟丙基甲基纤维素。储库可注射制剂也通过将物质截留在与身体组织相容的脂质体或微乳液中来制备。
药物组合物可通过任何合适的技术制备,并且不受用于其生产的任何特定方法的限制。例如,可将戊二酸新烟草碱与赋形剂和粘结剂合并,并且然后制粒。可将颗粒与任何剩余成分干混,并压制成固体形式如片剂。
固体剂型片剂、胶囊剂、丸剂和颗粒剂可制备为具有包衣和外壳,如肠溶衣和药物配制领域中熟知的其他包衣。它们可任选地含有乳浊剂并也可具有仅或优先在肠道的某一部分中或任选地以延迟或延长的方式释放一种或多种活性成分的组成。可使用的包埋组合物的实例包括聚合物质和蜡。用于延长释放的片剂制剂也见述于美国专利号5,942,244中。
药物组合物可含有任何常规的无毒的药学上可接受的载体、佐剂或媒介物。在一些情况下,可用可接受的药物或食品级酸、碱或缓冲剂来调节制剂的pH以增强配制组合物或其递送形式的稳定性。
本发明的化合物、晶体、多晶型形式和药物组合物可通过任何合适的途径施用。例如,所述组合物可经口、经肠胃外、通过吸入、局部地、经直肠、经鼻、经颊、经阴道、经由植入的储库施用,或作为膳食补充剂或食物摄入。如本文所用,术语肠胃外包括皮下、皮内、静脉内、肌内和颅内注射或输注技术。优选的施用途径包括经由干粉吸入器或蒸发气溶胶装置如热蒸发气溶胶装置吸入。热蒸发气溶胶装置见述于例如WO 02/098496、WO 02/098389和WO 03/095012中。
本发明的一个方面涉及用于根据本发明在热蒸发气溶胶装置中使用的本发明化合物、晶体或多晶型形式或药物组合物。戊二酸新烟草碱的量可随因素如热蒸发气溶胶装置的类型及是否存在其他活性组分而异。热蒸发气溶胶装置可具有各种类型的配置,其细节不构成本发明的一部分。一般来说,热蒸发气溶胶装置可以是一次性或用后即抛类型的,或者可以是可用液体生物碱组合物和/或含有液体组合物的药筒再填充的以便于再利用。
本发明的另一个方面涉及用于根据本发明在干粉吸入器中使用的本发明化合物、晶体或多晶型形式或药物组合物。使用干粉吸入器技术,装载到装置中的干粉戊二酸新烟草碱制剂的包装可含有不同的量,例如每剂0.01至10mg戊二酸新烟草碱、每剂0.05至5mg戊二酸新烟草碱或每剂0.1至1mg戊二酸新烟草碱,或者可使得不同的颗粒尺寸有不同浓度的戊二酸新烟草碱并可含有将调节吸入后戊二酸新烟草碱向身体中的释放和吸收的速率的制剂。它们也可具有影响味道、气味和颜色的pH调节剂和添加剂。可使用使用者的呼吸作为能源、或使用压缩气体或使用电池驱动带螺旋桨的电动马达或分散粉末的振动源来实现戊二酸新烟草碱粉末制剂的气溶胶化。
通过提供用于根据本发明在干粉吸入器或热蒸发气溶胶装置中使用的本发明化合物、晶体或多晶型物或药物组合物,可减少对吸传统香烟的渴望,同时最小化与尼古丁和其他烟草组分相关的毒性及其他不希望有的副作用。干粉吸入器或热蒸发气溶胶装置可根据满足渴望的需要使用,或每隔一定时间使用,如每天一次、每天两次或每天三次或更多次,具体取决于因素如活性组分的浓度和受试者的生理状况。
本发明因此还涉及包含本发明的化合物、晶体、多晶型物和/或药物组合物的无烟烟草产品。
所述无烟烟草产品含有粉末形式的本发明化合物、晶体、多晶型物和/或药物组合物。在一个实施方案中,无烟烟草产品因此含有烟草以及本发明的化合物、晶体、多晶型物和/或药物组合物。
在本发明的一个优选实施方案中,无烟烟草产品为包含粉状烟草及本发明的化合物、晶体、多晶型物和/或药物组合物的固体咬嘴(solid bit)。粉状烟草可由熏制的烟梗、烟片或两者(下文统称为“烟草材料”)制得。无烟烟草产品中烟草材料的相对比例取决于因素如烟叶的特定组成。固体咬嘴最常具有约10重量%至约80重量%、更经常约25重量%至约55重量%的粉状烟草。
优选地,将熏制的烟草材料粉化,例如研磨,以形成粉状烟草。这样将烟草材料研磨得足够细以产生易于吞咽的产品。或者,干燥烟草材料的提取物以形成粉末。在提取过程中,用溶剂(通常是水)或蒸汽提取熏制的烟草材料。所得溶液含有烟草的水溶性组分,包括尼古丁。然后根据需要干燥溶液并研磨以形成粉状烟草。
然后可使用粉状烟草来形成咬嘴。然而,在形成咬嘴之前,粉状烟草可能需要被加工形成较大的颗粒,如通过制粒或通过碾压和研磨。这样的过程将提供更容易形成咬嘴的颗粒,并形成在操作过程中和在包装中不会崩解的咬嘴。而且,较大的颗粒比较小的颗粒更容易操作并且不会形成与小粉末颗粒相关的“粉尘”。此外,较大的颗粒比粉末颗粒更容易压缩成咬嘴。这允许更高速的咬嘴配制和更容易的咬嘴加工。另外,使用制粒或碾压和压制将提供调味剂、着色剂等在整个最终咬嘴中的均匀分布。
本发明的其他方面涉及用于电子烟的本发明化合物、晶体、多晶型物和/或药物组合物,所述电子烟设计为提供不同范围的生物碱组合物,所述生物碱组合物包含本发明的化合物、晶体、多晶型物和/或药物组合物,以更有效地实现吸烟者通过吸传统香烟所获得的愉悦增强效果,同时避免或减少尼古丁暴露。在一个实施方案中,基于总生物碱重量计,生物碱组合物包含至少约25重量%的本发明化合物、晶体、多晶型物和/或药物组合物。在一些实例中,本发明的化合物、晶体、多晶型物和/或药物组合物是存在于组合物中的唯一生物碱,例如,本发明的化合物、晶体、多晶型物和/或药物组合物占总生物碱重量的100重量%。在其他实例中,除了本发明的化合物、晶体、多晶型物和/或药物组合物外,还可存在至多约75重量%的一种或多种其他生物碱,如尼古丁、降烟碱和/或阿那巴辛。例如,可以约50:1至约1:3、或约25:1至约1:2、约10:1至约3:2、或约5:1至约1:1的重量比(新烟草碱对尼古丁)组合本发明的化合物、晶体、多晶型物和/或药物组合物与尼古丁。
组合物中存在的本发明化合物、晶体、多晶型物和/或药物组合物的量可随因素如电子烟的类型及是否存在其他活性组分如尼古丁和/或其他生物碱而异。举例来说,本发明的化合物、晶体、多晶型物和/或药物组合物的量可在每总的一克组合物约0.1至约25mg、约0.5至约20mg、或约1至约10mg的范围内。
除了本发明的化合物、晶体、多晶型物和/或药物组合物外,基于总生物碱重量计,组合物还可含有至多约75重量%的一种或多种其他生物碱,如尼古丁、降烟碱和/或阿那巴辛。这样的生物碱可从烟草或其他植物材料中提取并使用已知的技术纯化,和/或使用已知的合成方法合成制备。可以约50:1至约1:3、或约25:1至约1:2、约10:1至约3:2、或约5:1至约1:1的重量比(新烟草碱对总的其他生物碱)组合本发明的化合物、晶体、多晶型物和/或药物组合物与另外的一种或多种生物碱,如尼古丁。
组合物通常含有其他组分如水、有机溶剂、甜味剂和/或调味剂等。在用于电子烟的液体组合物中常用的溶剂的实例包括多元醇如1,2-丙二醇(PG或MPG);一元醇如乙醇;乙酸乙酯;等。存在的水的量通常在约0.1重量%至约10重量%、常常约0.5重量%至约5重量%的范围内。存在的有机溶剂的量通常在约50重量%至约99重量%、常约75重量%至约95重量%的范围内。
如果需要,可向组合物中加入一种或多种调味剂,其非限制性实例包括胡椒薄荷、薄荷醇、冬青、留兰香、蜂胶、桉、肉桂等。基于组合物的总重量计,调味剂的总量通常在约0.5重量%至约15重量%、常约1重量%至约10重量%的范围内。
电子烟可具有各种类型的配置。一般来说,电子烟可以是一次性或用后即抛类型的,或者可以是可用液体生物碱组合物和/或含有液体组合物的药筒再填充的以便于再利用。电子烟的一个实例在US 15/679731的图1中示出。外壳的外壁上设置有进气口,所述外壳容纳LED、电池、电子电路板、常压腔、传感器、蒸气-液体分离器、雾化器、液体供应瓶、烟嘴、微动开关、气体出口和空气通道。电子电路板具有电子开关电路和高频发生器。传感器中设置有负压腔并通过波纹膜与传感器分开。雾化器中设置有雾化腔。设置有固定环用于将液体供应瓶锁定在液体供应瓶的一侧与外壳之间;并在液体供应瓶的另一侧上设置有气溶胶通道。其他细节见述于授予Hon的美国专利号7,832,410B2中,其公开内容通过引用整体并入本文。
通过提供含本发明的化合物、晶体、多晶型物和/或组合物作为显著的生物碱组分的平衡的生物碱组合物,可以制备电子烟,该电子烟将减少对吸传统香烟的渴望,同时最小化与尼古丁和其他烟草组分相关的毒性及其他不希望有的副作用。电子烟可根据满足渴望的需要使用,或每隔一定时间使用,如每天一次、每天两次或每天三次或更多次,具体取决于因素如活性组分的浓度和受试者的生理状况。
在一个替代的实施方案中,非烟草制剂含有生物碱组合物,所述生物碱组合物包含基于组合物的总生物碱重量计约25重量%至约95重量%的新烟草碱和约5重量%至约75重量%的第二生物碱。第二生物碱可以是尼古丁、降烟碱、阿那巴辛或它们中两种或更多种的组合。非烟草产品可呈压缩粉末、口香糖、胶囊、丸剂、锭剂等的固体咬嘴形式。术语“非烟草”指的是产品基本上不含烟叶或烟草提取物,但除了非烟草产品中存在的可从烟草提取并使用常规技术如液相色谱纯化的一些或所有生物碱之外。
可向非烟草产品中添加另外的组分成分以改善味道或稳定性。这样的另外的组分包括但不限于甜味剂、天然调味剂、人造调味剂、着色剂、抗氧化剂、防腐剂、螯合剂、粘度调节剂、张力调节剂(tonicifier)、气味剂、乳浊剂、悬浮剂、粘结剂、增稠剂及其混合物,包括但不限于黄原胶、羧甲基纤维素、羧乙基纤维素、羟丙基纤维素、甲基纤维素、微晶纤维素、淀粉、糊精、发酵乳清、豆腐、麦芽糊精、多元醇(包括糖醇,如山梨糖醇或甘露醇)、碳水化合物(例如,乳糖)、海藻酸丙二醇酯、结兰胶、瓜尔胶、果胶、黄蓍胶、阿拉伯树胶、刺槐豆胶、阿拉伯胶、明胶、甘露醇、天然和/或人造薄荷香料、三氯蔗糖、二氧化硅、硬脂酸、羟丙基甲基纤维素、硬脂酸镁、二氧化钛、天然釉料、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、柠檬酸三乙酯、柠檬酸、丁基化羟基甲苯(BHT)、甘油单酯和甘油二酯、聚山梨酯80等。
非烟草产品可呈各种形式,例如以经口服用,如丸剂、片剂、胶囊剂、软凝胶剂、软胶囊剂、液体剂、糖浆剂、混悬剂、散剂、含片、锭剂、口香糖、条等,或以通过其他途径施用,如肠胃外、通过吸入喷雾、局部地、经由植入的储库等。生物碱组合物也可制备为在食物或饮料中施用。例如,它们可以干燥或粉状产品供应以在使用前用水或其他合适的媒介物(例如,牛奶、果汁等)重构。
本文提供的化合物、晶体、多晶型物和/或药物组合物或任何其他组合物还可包含一种或多种维生素,如维生素A(视黄醇)、维生素B1(硫胺)、维生素C(抗坏血酸)、维生素D(骨化醇)、维生素D2(麦角骨化醇)、维生素D3(胆钙化醇)、维生素B2(核黄素)、维生素E(生育酚)、维生素B12(钴胺)、维生素K1(叶绿醌)、维生素B5(泛酸)、维生素B7(生物素)、维生素B6(吡哆醇)、维生素B3(烟酸)、维生素B9(叶酸)。合成维生素的方法是熟知的,并可从任何信誉良好的商业来源获得维生素。在一些实施方案中,本发明的化合物、晶体、多晶型物和/或药物组合物还包含维生素A。在一些实施方案中,本发明的化合物、晶体、多晶型物和/或药物组合物还包含维生素D3。在一些实施方案中,本发明的化合物、晶体、多晶型物和/或药物组合物还包含维生素A和维生素D3。
本发明的组合物中新烟草碱和维生素的量可变化。在一些实施方案中,所述化合物、晶体、多晶型物的量在约0.1mg至约10mg的范围内(例如,约0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、3.0、4.0、5.0、6.0、7.0、8.0、9.0或10mg)。
在一些实施方案中,维生素A的量在约200至约500IU的范围内(例如,约200、250、300、350、400、401、402、403、404、405、406、407、408、409、410、411、412、413、414、415、416、417、418、419、420、450、475或500IU)。维生素A可例如以视黄醇乙酸酯提供。
在一些实施方案中,维生素D3的量在约15IU至约50IU的范围内(例如,约15、20、25、26、27、28、29、30、31、32、33、34、35、40、45或50IU)。维生素D3可以胆钙化醇提供。
在一些实施方案中,所述化合物、晶体和/或多晶型物与维生素A以相等的比例提供(例如,各1mg)。在一些实施方案中,可每天一次、两次或三次服用含1mg所述化合物、晶体和/或多晶型物的一种或多种锭剂。在一些实施方案中,日剂量不超过1、2、3、4、5或6个锭剂。在一些实施方案中,日剂量可超过1、2、3、4、5或6个锭剂。在一些实施方案中,产品呈锭剂的形式,该锭剂含:1mg本发明的化合物、晶体、多晶型物和/或药物组合物;417IU的维生素A(以视黄醇乙酸酯);33IU的维生素D3(以胆钙化醇);及甘露醇、天然和人造薄荷香料、三氯蔗糖、二氧化硅、硬脂酸、羟丙基甲基纤维素、硬脂酸镁、二氧化钛、天然釉料、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、柠檬酸三乙酯、柠檬酸、BHT、甘油单酯和甘油二酯及聚山梨酯80。
在本说明书中,引用了包括专利申请和科学文献在内的许多文件。这些文件的公开内容虽然不认为与本发明的可专利性相关,但其通过引用整体并入本文。更具体地,所有参考文件均通过引用并入,其程度就好像每一个单独的文件被明确地且一个一个单独地指出通过引用并入一样。
现在参考以下实施例描述本发明,这些实施例仅是示意性的而不应解释为对本发明的范围的限制。
实施例
实施例1
戊二酸新烟草碱的制备
通过以下方法将新烟草碱游离碱转化为1:1的戊二酸新烟草碱:
a)在25℃下向戊二酸(16.5g,125mmol,1.00当量)在乙腈(500mL)中的溶液中逐滴加入新烟草碱(20.0g,125mmol,1.00当量),并将混合物于25℃下搅拌1小时。TLC(二氯甲烷:甲醇=20:1)显示新烟草碱(Rf=0.5)被消耗。过滤混合物。收集滤饼并浓缩至干,得到呈灰白色固体的戊二酸新烟草碱(30.0g,103mmol,收率82.2%,纯度100%)。
b)向新烟草碱(11.6g,72mmol)在乙腈(700ml)中的溶液中加入戊二酸((9.6g,72mmol)。反应混合物变得浑浊。然后加热反应混合物,直至获得澄清的黄色溶液。让混合物冷却至室温(20℃)并搅拌2小时。出现黏糊糊的固体,用刮刀刮下该固体。将混合物再搅拌30分钟,并将所得浅黄色固体在氩气气氛下过滤,用乙腈(500ml)洗涤并在45℃下减压干燥45分钟,得到呈浅黄色固体的戊二酸新烟草碱(18.3g,87%)。
1HNMR(D2O),δ:8.84-8.45(m,2H),7.99(d,J=7.8Hz,1H),7.59-7.55(m,1H),6.08(d,J=8.4Hz,1H),5.85(d,J=10.4Hz,1H),4.63-4.59(m,1H),3.97-3.87(m,1H),3.81-3.70(m,1H),2.80-2.53(m,2H),2.25(t,J=7.6Hz,4H),1.82-1.74(m,2H)。使用配备PDA检测器的Waters Acquity UPLC H-class和SQD质谱仪评估戊二酸新烟草碱的化学纯度,其中使用柱BEH C18,2.1×50mm,1.7μM梯度运行,在261nM下检测。戊二酸新烟草碱的保留时间为1.125分钟,纯度为99.41%,[M+H]+161.0(图3、4)。戊二酸新烟草碱(图5)和新烟草碱游离碱(图6)的FTIR光谱的比较指示出N-H条带的变化,表明确认形成了盐。
将以这种方式获得的戊二酸新烟草碱加热至回流后在冷却的同时在2.5mL乙腈中重结晶。回收固相并干燥。
使用零背景有机硅晶片(具有9mm腔)通过X-射线粉末衍射(XRPD)在2-40°2θ之间分析戊二酸新烟草碱盐。通过uHPLC发现其纯度高于99%。
实施例2
戊二酸新烟草碱的离子色谱
进行离子色谱分析来分析戊二酸新烟草碱的化学计量(图11)。将戊二酸新烟草碱溶解在IC级水(90μg/ml)中,使用配备Metrohm 889冷却自动进样器的Metrohm 940高压梯度离子色谱仪分析该溶液,洗脱溶液为3.2mM的碳酸钠和1mM的碳酸氢钠,再生溶液为150mM的硫酸/100mM的草酸,并使用柱A Supp 5(IC004或等同物)。对戊二酸新烟草碱分析两次,结果汇总在下表中:
为98.0%的理论回收率证实戊二酸盐以1:1的新烟草碱:戊二酸比率存在。离子色谱法的结果与质子NMR波谱(图2)一致。
实施例3
戊二酸新烟草碱的动态蒸气吸附测试
将戊二酸新烟草碱(20mg)直接分配到预先称重的样本盘中并转移至仪器(DVS1Advantage)。应用双周期0-90-0-90-0%RH方法,以10%RH为步进。样品在第一吸附周期中显示出55%的质量增加,而大部分质量增加发生在70%RH以上。第一解吸周期显示出约50%的质量损失,在第二周期中重复上述过程,第二吸附周期中仅显示出约50%的质量增加。在等温线中确认此质量增加,表明起始重量和最终重量之间有约5%的质量增加(图10)。
实施例4
戊二酸新烟草碱的卡尔费休滴定
使用100mg样品在配备860烘箱的Metrohm 852组合体积/库仑卡尔费休滴定仪上测定所得戊二酸新烟草碱中水的量。发现该戊二酸新烟草碱含0.21重量/重量%的水。
实施例5
戊二酸新烟草碱的稳定性评估
在T=0时分析戊二酸新烟草碱,随后将等分试样在温育箱中于加速条件(40℃/75%RH)下储存在带螺帽盖的玻璃小瓶中,保存7天,然后进行进一步的分析。在T=0、3和7天时目测评估所储存的样品的稳定性,未观察到颜色的变化或任何潮解的迹象。还使用TGA、XRPD和HPLC-UV在T=0时和T=7天后再次评估所储存的样品。
T=7天的样品的TGA热谱图显示出在20-130℃之间为0.5%的轻微质量损失,其后发生了降解,并在150℃至400℃之间发生了80%的质量损失。T=0天和T=7天时热谱图的叠加显示出很小的差异,仅有2%的质量损失差异。因此可以看出,当戊二酸新烟草碱在40℃/75%RH下储存7天时热稳定性没有变化。
T=7天的样品的XRPD图谱与T=0的图谱未显示出差异并且材料保持不变,因此表明当在40℃/75%RH下储存7天时戊二酸新烟草碱的结晶形式没有变化。
为了通过HPLC-UV评价稳定性,通过称取约10mg新烟草碱和戊二酸新烟草碱、溶解在50ml容量瓶中并加入去离子水至刻度线来制备新烟草碱和戊二酸新烟草碱的200μg/ml样品溶液,各制备两个平行样。在HPLC方法优化过程中已对运行时间和梯度进行调整以便进行稳定性分析。在方法优化之后进行了强制降解试验以通过确定戊二酸新烟草碱样品中存在的任何降解物或杂质来帮助计划的稳定性评估分析。强制降解试验在五种条件——酸、碱、对照、热和氧化——下分析样品并在T=0、4和18小时时进行测试。表现出任何降解(峰面积>1%)的唯一样品是氧化样品,其中添加了3%的过氧化氢(H2O2)。
为了进行环境稳定性评估,向透明的玻璃培养皿中称取戊二酸新烟草碱(100mg)并在通风橱中于环境条件下敞口保持7天。在T=0、3和7天时对所储存的样品进行目测评估。未观察到颜色的变化或任何潮解的迹象(图12)。
对比例1
柠檬酸新烟草碱的制备
将新烟草碱游离碱(160mg,1mmol)溶解在无水丙酮(2.5ml)中。向所形成的溶液中加入无水柠檬酸(192mg,1mmol)在无水丙酮(3ml,需要超声处理)中的溶液,在氮气下搅拌。将混合物搅拌2小时,然后在氮气覆层下过滤。用少量无水丙酮洗涤固体并真空干燥。取得340mg(96.6%)的柠檬酸新烟草碱产量。由于已证实该盐极吸湿,故将其储存在氮气下。通过质子NMR确认化学结构和化学计量。柠檬酸盐的固体形式含有捕获的丙酮。
类似地制备酒石酸盐形式并发现酒石酸盐(图13)和柠檬酸盐(图14)(在美国专利8,207,346和美国专利8,557,999中公开)均以非晶形式存在。
一般程序
使用40μL铝盘在Perkin Elmer DSC 8000上进行调制差示扫描量热法(mDSC)。使用分析天平称取约6mg的每种样品置于预先称重的铝DSC盘上。使用温度调制程序在氮气气氛下将样品以5℃为步进从-70℃加热至175℃。检查数据看是否存在任何热事件。
使用衰减全反射(ATR)模块在Jasco 420FT-IR上进行傅里叶变换红外光谱法(FT-IR)。向ATR模块的晶体上放置1-2mg样品并固定就位。使用Jasco Spectra Manager软件v1.51.00进行分析。
使用9mm腔和平板样品保持器在Bruker D8 Advance XRPD上进行粉末X-射线衍射(XRPD)。通过将样品涂布到装有零背景硅晶片(5 1 0)的样品保持器上来制备样品。使用在40kV、40mA下工作的Cu KαX-射线源和Lynx Eye TM检测器来进行分析;所有样品均在2-40°2θ的范围内分析。
在Perkin Elmer PYRIS 1TGA上在陶瓷坩埚中使用40μL铝盘(通风的)进行热重分析(TGA)。在氮气流下以10℃/分钟的速率(另有说明除外)将样品从室温加热至400℃。
在配备有5mm QNP探针的Bruker 400Avance波谱仪上进行1H核磁共振波谱法(NMR)。将5-7mg样品溶解在氘代甲醇或二甲基亚砜中。将溶液转移到场匹配的5mm NMR管中进行分析。
使用DVS控制软件v1.0.6.0在SMS DVS动态蒸气吸附仪器上进行动态蒸气吸附(DVS)。在不锈钢DVS篮中称取30mg样品,然后提交进行分析。在0-90%RH的范围上分析样品,每个湿度阶段的最大时间为6小时。每个样品都经历两个周期。以0-90%RH的重量百分数变化进行分析,并检查了等温图。在DVS后对所有样品进行XRPD分析。
通过1H-NMR波谱法确认戊二酸新烟草碱的化学完整性和化学计量。
在配备Metrohm 889冷却自动进样器的Metrohm 940高压梯度离子色谱仪上进行离子色谱法,洗脱溶液为3.2mM的碳酸钠和1mM的碳酸氢钠,再生溶液为150mM的硫酸/100mM的草酸。
该样品的DVS分析显示,在第一吸附周期中在0-90%RH之间质量吸收为55%,然后在解吸过程中损失质量,直至其达到高于起始质量的5%。这表明水分的增加。第二吸附周期显示出50%的质量吸收,并且在第二解吸后,最终质量比起始质量大5%。这表明在第一吸附周期中获得的水被保留。该样品的等温线图进一步确认了这一点。
在将样品留置过夜后,发现其已重结晶为固体形式。在比较DVS前后样品的X-射线衍射图谱时,观察到匹配。这表明DVS前后晶体形式是相同的。
戊二酸新烟草碱具有有利的性质如高结晶度、形态、对多晶型转化和/或脱水的热和力学稳定性、储存稳定性、低的残余溶剂含量、较低的吸湿性程度、可流动性以及有利的加工和操作特性。
Claims (19)
1.一种化合物,所述化合物为3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐或其药学上可接受的溶剂化物。
2.根据权利要求1所述的化合物,其中所述3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐具有1:1的3-(1,2,3,6-四氢吡啶-2-基)吡啶与戊二酸盐的摩尔比。
3.根据权利要求1或2所述的化合物,其中所述3-[1,2,3,6-四氢吡啶-2-基]吡啶为3-[(2S)-1,2,3,6-四氢吡啶-2-基]吡啶。
6.根据权利要求1至5中任一项所述的化合物的晶体。
7.根据权利要求1至5中任一项所述的化合物或根据权利要求6所述的晶体的多晶型形式。
8.根据权利要求7所述的多晶型形式,其中所述多晶型形式具有大体上如图1所示的X-射线粉末衍射图谱(CuKα)。
9.根据权利要求7或8所述的多晶型形式,其中所述多晶型形式具有包括一个或多个选自8.0±0.2°2θ、11.0±0.2°2θ、13.3±0.2°2θ、16.5±0.2°2θ、18.0±0.2°2θ、20.7±0.2°2θ、21.0±0.2°2θ、21.4±0.2°2θ、22.0±0.2°2θ、22.3±0.2°2θ、23.3±0.2°2θ和24.5±0.2°2θ的峰的X-射线粉末衍射图谱(CuKα)。
10.根据权利要求1至5中任一项所述的化合物、根据权利要求6所述的晶体或根据权利要求7至9中任一项所述的多晶型形式作为药剂的用途。
11.根据权利要求1至5中任一项所述的化合物、根据权利要求6所述的晶体或根据权利要求7至9中任一项所述的多晶型形式在物质成瘾或炎症的治疗或预防中的用途。
12.一种用于治疗或预防物质成瘾或炎症的药物组合物,所述组合物包含药学有效量的根据权利要求1至5中任一项所述的化合物、根据权利要求6所述的晶体或根据权利要求7至9中任一项所述的多晶型形式中的一种或多种,任选地与一种或多种药学上可接受的赋形剂一起。
13.一种用于在有此需要的人或非人动物患者中治疗或预防尼古丁成瘾或炎症的方法,其中所述方法包括向所述患者施用治疗有效量的根据权利要求1至5中任一项所述的化合物、根据权利要求6所述的晶体、根据权利要求7至9中任一项所述的多晶型形式或根据权利要求12所述的药物组合物中的至少之一。
14.一种用于制备根据权利要求1至5中任一项所述的化合物、根据权利要求6所述的晶体或根据权利要求7至9中任一项所述的多晶型形式的方法,所述方法包括步骤:
制备包含3-[1,2,3,6-四氢吡啶-2-基]吡啶、戊二酸和溶剂的溶液,
使得形成3-[1,2,3,6-四氢吡啶-2-基]吡啶与戊二酸的盐,以及
回收3-[1,2,3,6-四氢吡啶-2-基]吡啶戊二酸盐。
15.根据权利要求14所述的方法,其中在3-[1,2,3,6-四氢吡啶-2-基]吡啶、戊二酸和溶剂的所述溶液的制备中使用的溶剂包括2-甲基四氢呋喃、乙腈和/或乙酸乙酯。
16.用于根据权利要求11的用途的根据权利要求1至5中任一项所述的化合物、根据权利要求6所述的晶体、根据权利要求7至9中任一项所述的多晶型形式,或者用于根据权利要求12的用途的所述药物组合物,其中所述物质选自尼古丁、可卡因、海洛因、大麻和酒精。
17.用于根据权利要求11的用途的根据权利要求1至5中任一项所述的化合物、根据权利要求6所述的晶体、根据权利要求7至9中任一项所述的多晶型形式,或者用于根据权利要求12的用途的所述药物组合物,其中所述炎症选自阿尔茨海默氏病、甲状腺炎和多发性硬化症。
18.用于根据权利要求11的用途的根据权利要求1至5中任一项所述的化合物、根据权利要求6所述的晶体、根据权利要求7至9中任一项所述的多晶型形式,或者用于根据权利要求12的用途的所述药物组合物,其在干粉吸入器中。
19.用于根据权利要求11的用途的根据权利要求1至5中任一项所述的化合物、根据权利要求6所述的晶体、根据权利要求7至9中任一项所述的多晶型形式,或者用于根据权利要求12的用途的所述药物组合物,其在热蒸发气溶胶装置中。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP18213200.1 | 2018-12-17 | ||
EP18213200 | 2018-12-17 | ||
PCT/EP2019/085598 WO2020127225A1 (en) | 2018-12-17 | 2019-12-17 | 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine glutarate or a pharmaceutically acceptable solvate thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113039180A true CN113039180A (zh) | 2021-06-25 |
Family
ID=64744512
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980076050.9A Pending CN113039180A (zh) | 2018-12-17 | 2019-12-17 | 3-(1,2,3,6-四氢吡啶-2-基)吡啶戊二酸盐或其药学上可接受的溶剂化物 |
Country Status (19)
Country | Link |
---|---|
US (1) | US20210395218A1 (zh) |
EP (1) | EP3898607B1 (zh) |
JP (1) | JP2022514283A (zh) |
KR (1) | KR20210104666A (zh) |
CN (1) | CN113039180A (zh) |
AU (1) | AU2019407661A1 (zh) |
BR (1) | BR112021009580A2 (zh) |
CA (1) | CA3116524A1 (zh) |
CL (1) | CL2021001583A1 (zh) |
CO (1) | CO2021009186A2 (zh) |
EC (1) | ECSP21052586A (zh) |
ES (1) | ES2964561T3 (zh) |
HU (1) | HUE063731T2 (zh) |
IL (1) | IL283923A (zh) |
MX (1) | MX2021006867A (zh) |
PH (1) | PH12021550875A1 (zh) |
PL (1) | PL3898607T3 (zh) |
WO (1) | WO2020127225A1 (zh) |
ZA (1) | ZA202102058B (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022049487A1 (en) | 2020-09-03 | 2022-03-10 | Philip Morris Products S.A. | Low hygroscopicity active powder compositions |
MX2023002467A (es) | 2020-09-03 | 2023-03-23 | Philip Morris Products Sa | Composiciones en polvo activas de baja higroscopicidad secadas por atomizado. |
WO2022049486A1 (en) | 2020-09-03 | 2022-03-10 | Philip Morris Products S.A. | Freeze dried low hygroscopicity active powder compositions |
JP2024503610A (ja) * | 2021-01-07 | 2024-01-26 | フィリップ・モーリス・プロダクツ・ソシエテ・アノニム | アナタビンを含む組成物およびその使用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110237627A1 (en) * | 2010-03-23 | 2011-09-29 | Rock Creek Pharmaceuticals, Inc. | Methods of synthesizing anatabine |
WO2011119722A2 (en) * | 2010-03-23 | 2011-09-29 | Rock Creek Pharmaceuticals, Inc. | Use of anatabine to treat inflammation and methods of synthesizing anatabine |
CN104169269A (zh) * | 2011-08-29 | 2014-11-26 | Rcp发展股份有限公司 | 用于抗炎支持的产品 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5582837A (en) | 1992-03-25 | 1996-12-10 | Depomed, Inc. | Alkyl-substituted cellulose-based sustained-release oral drug dosage forms |
US5972389A (en) | 1996-09-19 | 1999-10-26 | Depomed, Inc. | Gastric-retentive, oral drug dosage forms for the controlled-release of sparingly soluble drugs and insoluble matter |
US6210710B1 (en) | 1997-04-28 | 2001-04-03 | Hercules Incorporated | Sustained release polymer blend for pharmaceutical applications |
US5942244A (en) | 1997-07-31 | 1999-08-24 | Farmo-Nat Ltd. | Local oral herbal slow release tablets |
US6090411A (en) | 1998-03-09 | 2000-07-18 | Temple University | Monolithic tablet for controlled drug release |
US7458374B2 (en) | 2002-05-13 | 2008-12-02 | Alexza Pharmaceuticals, Inc. | Method and apparatus for vaporizing a compound |
US7766013B2 (en) | 2001-06-05 | 2010-08-03 | Alexza Pharmaceuticals, Inc. | Aerosol generating method and device |
US6723340B2 (en) | 2001-10-25 | 2004-04-20 | Depomed, Inc. | Optimal polymer mixtures for gastric retentive tablets |
CN2719043Y (zh) | 2004-04-14 | 2005-08-24 | 韩力 | 雾化电子烟 |
US8241680B2 (en) | 2010-06-30 | 2012-08-14 | Rock Creek Pharmaceuticals, Inc. | Nutraceutical product containing anatabine and yerba maté |
WO2015009500A1 (en) | 2013-07-19 | 2015-01-22 | Williams Jonnie R | Volatilized delivery of anatabine for treatment of substance addiction |
-
2019
- 2019-12-17 AU AU2019407661A patent/AU2019407661A1/en active Pending
- 2019-12-17 BR BR112021009580-2A patent/BR112021009580A2/pt unknown
- 2019-12-17 HU HUE19829499A patent/HUE063731T2/hu unknown
- 2019-12-17 MX MX2021006867A patent/MX2021006867A/es unknown
- 2019-12-17 WO PCT/EP2019/085598 patent/WO2020127225A1/en unknown
- 2019-12-17 US US17/289,794 patent/US20210395218A1/en active Pending
- 2019-12-17 KR KR1020217015007A patent/KR20210104666A/ko unknown
- 2019-12-17 ES ES19829499T patent/ES2964561T3/es active Active
- 2019-12-17 CN CN201980076050.9A patent/CN113039180A/zh active Pending
- 2019-12-17 EP EP19829499.3A patent/EP3898607B1/en active Active
- 2019-12-17 CA CA3116524A patent/CA3116524A1/en active Pending
- 2019-12-17 JP JP2021534811A patent/JP2022514283A/ja active Pending
- 2019-12-17 PL PL19829499.3T patent/PL3898607T3/pl unknown
-
2021
- 2021-03-26 ZA ZA2021/02058A patent/ZA202102058B/en unknown
- 2021-04-15 PH PH12021550875A patent/PH12021550875A1/en unknown
- 2021-06-13 IL IL283923A patent/IL283923A/en unknown
- 2021-06-16 CL CL2021001583A patent/CL2021001583A1/es unknown
- 2021-07-14 CO CONC2021/0009186A patent/CO2021009186A2/es unknown
- 2021-07-16 EC ECSENADI202152586A patent/ECSP21052586A/es unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110237627A1 (en) * | 2010-03-23 | 2011-09-29 | Rock Creek Pharmaceuticals, Inc. | Methods of synthesizing anatabine |
WO2011119722A2 (en) * | 2010-03-23 | 2011-09-29 | Rock Creek Pharmaceuticals, Inc. | Use of anatabine to treat inflammation and methods of synthesizing anatabine |
CN104169269A (zh) * | 2011-08-29 | 2014-11-26 | Rcp发展股份有限公司 | 用于抗炎支持的产品 |
Also Published As
Publication number | Publication date |
---|---|
EP3898607A1 (en) | 2021-10-27 |
MX2021006867A (es) | 2021-07-02 |
AU2019407661A1 (en) | 2021-04-29 |
ZA202102058B (en) | 2022-09-28 |
EP3898607B1 (en) | 2023-10-18 |
CL2021001583A1 (es) | 2021-11-26 |
WO2020127225A1 (en) | 2020-06-25 |
ES2964561T3 (es) | 2024-04-08 |
KR20210104666A (ko) | 2021-08-25 |
CA3116524A1 (en) | 2020-06-25 |
CO2021009186A2 (es) | 2021-08-30 |
PL3898607T3 (pl) | 2024-03-18 |
EP3898607C0 (en) | 2023-10-18 |
US20210395218A1 (en) | 2021-12-23 |
BR112021009580A2 (pt) | 2021-08-17 |
JP2022514283A (ja) | 2022-02-10 |
HUE063731T2 (hu) | 2024-01-28 |
ECSP21052586A (es) | 2021-08-31 |
PH12021550875A1 (en) | 2021-10-18 |
IL283923A (en) | 2021-07-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3898607B1 (en) | 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine glutarate or a pharmaceutically acceptable solvate thereof | |
EP2964223B1 (en) | Compounds inhibiting leucine-rich repeat kinase enzyme activity | |
EP3190889B1 (en) | Compounds inhibiting leucine-rich repeat kinase enzyme activity | |
AU2010224485B2 (en) | Use of pharmaceutical compositions containing mesembrenone | |
US20150080447A1 (en) | Sceletium Extract and Uses Thereof | |
US20180370965A1 (en) | Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same | |
AU2017340403B2 (en) | Small molecule AMPK activators | |
EP2496568B1 (en) | Polymorph of 3-(substituteddihydroisoindolinone-2-yl)-2,6-dioxopiperidine, and pharmaceutical compositions thereof | |
CN109843300B (zh) | 一种化合物的结晶多晶型形式 | |
EP3953345B1 (en) | Pyridine rings containing derivatives as malt1 inhibitors | |
KR102255957B1 (ko) | 신규한 디벤조옥사포스피닌 옥사이드 유도체 화합물 및 이를 포함하는 퇴행성 질환의 예방 또는 치료용 약제학적 조성물 | |
EP3994141A1 (en) | Modulators of the nmda receptor | |
EP3458440B1 (en) | Pyridinethiones, pharmaceutical compositions thereof, and their therapeutic use for treating a proliferative, inflammatory, neurodegenerative, or immune-mediated disease | |
TWI831325B (zh) | 作為atr抑制劑的萘啶衍生物及其製備方法 | |
CN108853102B (zh) | 作用于Dectin-1的稠合吖啶衍生物及其用途 | |
EP4180428A1 (en) | Crystalline imidazo[4,5-b]pyridine compound, pharmaceutical compositions, and their use in treating medical conditions | |
HU211635A9 (en) | Pharmaceutically useful bicyclolactam derivative | |
JP2004511525A (ja) | 退行性脳神経系疾患の予防および治療効果を有するハンゲショウ抽出物 | |
WO2023213739A1 (en) | Nicotinic acetylcholine receptor ligands | |
CN116761599A (zh) | 氘代或部分氘代的n,n-二甲基色胺化合物 | |
US20220402919A1 (en) | Cyclic amide-containing pyridyl xanthines as a2b antagonists | |
CN118063445A (zh) | 吡咯烷酰胺衍生物及其用途 | |
CN117143074A (zh) | 3-苄氧基-6-吡啶基哒嗪类化合物及其制备方法和用途 | |
WO2013184806A1 (en) | Inhibitors of respiratory syncytial virus | |
CN113423709A (zh) | 三嗪酮并咪唑类化合物及其医药用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |