CN110709071A - 用于施用某些vmat2抑制剂的方法 - Google Patents
用于施用某些vmat2抑制剂的方法 Download PDFInfo
- Publication number
- CN110709071A CN110709071A CN201780088736.0A CN201780088736A CN110709071A CN 110709071 A CN110709071 A CN 110709071A CN 201780088736 A CN201780088736 A CN 201780088736A CN 110709071 A CN110709071 A CN 110709071A
- Authority
- CN
- China
- Prior art keywords
- composition
- vmat2 inhibitor
- disorder
- administered
- vmat2
- 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
- 239000003112 inhibitor Substances 0.000 title claims abstract description 124
- 238000000034 method Methods 0.000 title claims abstract description 73
- GEJDGVNQKABXKG-CFKGEZKQSA-N [(2r,3r,11br)-9,10-dimethoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1h-benzo[a]quinolizin-2-yl] (2s)-2-amino-3-methylbutanoate Chemical compound C1CN2C[C@@H](CC(C)C)[C@H](OC(=O)[C@@H](N)C(C)C)C[C@@H]2C2=C1C=C(OC)C(OC)=C2 GEJDGVNQKABXKG-CFKGEZKQSA-N 0.000 claims abstract description 140
- 229950006411 valbenazine Drugs 0.000 claims abstract description 136
- 239000000411 inducer Substances 0.000 claims abstract description 43
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 230000000155 isotopic effect Effects 0.000 claims abstract description 36
- MLAYZCMWRNQKQX-UHFFFAOYSA-N 2-hydroxy-1h-isoquinoline Chemical compound C1=CC=C2C=CN(O)CC2=C1 MLAYZCMWRNQKQX-UHFFFAOYSA-N 0.000 claims abstract description 20
- 108010020033 Vesicular Monoamine Transport Proteins Proteins 0.000 claims abstract description 15
- 102000009659 Vesicular Monoamine Transport Proteins Human genes 0.000 claims abstract description 15
- 102000018832 Cytochromes Human genes 0.000 claims abstract description 12
- 108010052832 Cytochromes Proteins 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims description 102
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 62
- 208000035475 disorder Diseases 0.000 claims description 55
- -1 methoxy-d Chemical class 0.000 claims description 49
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 47
- 229960001225 rifampicin Drugs 0.000 claims description 47
- 239000012458 free base Substances 0.000 claims description 39
- 230000036470 plasma concentration Effects 0.000 claims description 32
- 208000000269 Hyperkinesis Diseases 0.000 claims description 27
- 102000004328 Cytochrome P-450 CYP3A Human genes 0.000 claims description 25
- 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 claims description 25
- 208000012902 Nervous system disease Diseases 0.000 claims description 20
- 208000020016 psychiatric disease Diseases 0.000 claims description 20
- 208000025966 Neurological disease Diseases 0.000 claims description 19
- 230000000926 neurological effect Effects 0.000 claims description 19
- 239000002775 capsule Substances 0.000 claims description 17
- 230000001225 therapeutic effect Effects 0.000 claims description 13
- 208000019022 Mood disease Diseases 0.000 claims description 11
- 230000001965 increasing effect Effects 0.000 claims description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 11
- 208000017194 Affective disease Diseases 0.000 claims description 10
- 208000023105 Huntington disease Diseases 0.000 claims description 10
- 238000011260 co-administration Methods 0.000 claims description 10
- 206010008748 Chorea Diseases 0.000 claims description 9
- 206010044565 Tremor Diseases 0.000 claims description 8
- 208000012601 choreatic disease Diseases 0.000 claims description 8
- 208000000130 Cytochrome P-450 CYP3A Inducers Diseases 0.000 claims description 7
- 235000017309 Hypericum perforatum Nutrition 0.000 claims description 7
- 244000141009 Hypericum perforatum Species 0.000 claims description 7
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 claims description 6
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 claims description 6
- 229960000623 carbamazepine Drugs 0.000 claims description 6
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical group C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims description 6
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 claims description 6
- 229960002036 phenytoin Drugs 0.000 claims description 6
- 208000014094 Dystonic disease Diseases 0.000 claims description 5
- 208000002033 Myoclonus Diseases 0.000 claims description 5
- 208000010118 dystonia Diseases 0.000 claims description 5
- 230000003389 potentiating effect Effects 0.000 claims description 5
- 206010026749 Mania Diseases 0.000 claims description 4
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 4
- 208000016620 Tourette disease Diseases 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 201000000980 schizophrenia Diseases 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 206010003591 Ataxia Diseases 0.000 claims description 3
- 208000020925 Bipolar disease Diseases 0.000 claims description 3
- 206010008025 Cerebellar ataxia Diseases 0.000 claims description 3
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 claims description 3
- 208000033895 Choreoacanthocytosis Diseases 0.000 claims description 3
- XWLUWCNOOVRFPX-UHFFFAOYSA-N Fosphenytoin Chemical compound O=C1N(COP(O)(=O)O)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 XWLUWCNOOVRFPX-UHFFFAOYSA-N 0.000 claims description 3
- 208000001914 Fragile X syndrome Diseases 0.000 claims description 3
- 101000667092 Homo sapiens Vacuolar protein sorting-associated protein 13A Proteins 0.000 claims description 3
- 208000009625 Lesch-Nyhan syndrome Diseases 0.000 claims description 3
- 208000016285 Movement disease Diseases 0.000 claims description 3
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 3
- 208000005793 Restless legs syndrome Diseases 0.000 claims description 3
- 208000006289 Rett Syndrome Diseases 0.000 claims description 3
- 208000035317 Total hypoxanthine-guanine phosphoribosyl transferase deficiency Diseases 0.000 claims description 3
- 102100039114 Vacuolar protein sorting-associated protein 13A Human genes 0.000 claims description 3
- ZWBTYMGEBZUQTK-PVLSIAFMSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c4NC5(CCN(CC(C)C)CC5)N=c4c(=NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C ZWBTYMGEBZUQTK-PVLSIAFMSA-N 0.000 claims description 3
- 208000029560 autism spectrum disease Diseases 0.000 claims description 3
- 201000008675 chorea-acanthocytosis Diseases 0.000 claims description 3
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 claims description 3
- 229960004671 enzalutamide Drugs 0.000 claims description 3
- 235000013305 food Nutrition 0.000 claims description 3
- 229960000693 fosphenytoin Drugs 0.000 claims description 3
- 229960000350 mitotane Drugs 0.000 claims description 3
- 208000007431 neuroacanthocytosis Diseases 0.000 claims description 3
- 230000009251 neurologic dysfunction Effects 0.000 claims description 3
- 208000015015 neurological dysfunction Diseases 0.000 claims description 3
- 229960000689 nevirapine Drugs 0.000 claims description 3
- 229960001412 pentobarbital Drugs 0.000 claims description 3
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 claims description 3
- 229960002695 phenobarbital Drugs 0.000 claims description 3
- DQMZLTXERSFNPB-UHFFFAOYSA-N primidone Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NCNC1=O DQMZLTXERSFNPB-UHFFFAOYSA-N 0.000 claims description 3
- 229960002393 primidone Drugs 0.000 claims description 3
- 229960000885 rifabutin Drugs 0.000 claims description 3
- GDJZZWYLFXAGFH-UHFFFAOYSA-M xylenesulfonate group Chemical group C1(C(C=CC=C1)C)(C)S(=O)(=O)[O-] GDJZZWYLFXAGFH-UHFFFAOYSA-M 0.000 claims description 3
- UFSKUSARDNFIRC-UHFFFAOYSA-N lumacaftor Chemical compound N1=C(C=2C=C(C=CC=2)C(O)=O)C(C)=CC=C1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 UFSKUSARDNFIRC-UHFFFAOYSA-N 0.000 claims description 2
- 229960000998 lumacaftor Drugs 0.000 claims description 2
- 125000003580 L-valyl group Chemical class [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 claims 2
- 208000028017 Psychotic disease Diseases 0.000 claims 2
- 238000013019 agitation Methods 0.000 claims 2
- 208000022610 schizoaffective disease Diseases 0.000 claims 2
- 102100034333 Synaptic vesicular amine transporter Human genes 0.000 description 83
- 239000008194 pharmaceutical composition Substances 0.000 description 77
- 239000002552 dosage form Substances 0.000 description 57
- 150000001875 compounds Chemical class 0.000 description 40
- WEQLWGNDNRARGE-DJIMGWMZSA-N (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-ol Chemical compound C1CN2C[C@@H](CC(C)C)[C@H](O)C[C@@H]2C2=C1C=C(OC)C(OC)=C2 WEQLWGNDNRARGE-DJIMGWMZSA-N 0.000 description 39
- 239000004480 active ingredient Substances 0.000 description 39
- 239000003814 drug Substances 0.000 description 36
- 229940079593 drug Drugs 0.000 description 35
- RPHPRWCGGJGIHI-WGQQHEPDSA-N [(2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-yl] (2S)-2-amino-3-hydroxy-3-methylbutanoate Chemical compound COc1cc2CCN3C[C@@H](CC(C)C)[C@@H](C[C@@H]3c2cc1OC)OC(=O)[C@@H](N)C(C)(C)O RPHPRWCGGJGIHI-WGQQHEPDSA-N 0.000 description 33
- 230000000694 effects Effects 0.000 description 32
- 239000002207 metabolite Substances 0.000 description 30
- 102000004190 Enzymes Human genes 0.000 description 26
- 108090000790 Enzymes Proteins 0.000 description 26
- 235000002639 sodium chloride Nutrition 0.000 description 25
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 23
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 23
- 229910052805 deuterium Inorganic materials 0.000 description 21
- 239000003826 tablet Substances 0.000 description 21
- 239000000546 pharmaceutical excipient Substances 0.000 description 20
- 229920001577 copolymer Polymers 0.000 description 19
- 238000013270 controlled release Methods 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 229920002301 cellulose acetate Polymers 0.000 description 17
- 239000000126 substance Substances 0.000 description 17
- 239000013543 active substance Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000000843 powder Substances 0.000 description 15
- 239000000825 pharmaceutical preparation Substances 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- 239000012528 membrane Substances 0.000 description 13
- 229920002472 Starch Polymers 0.000 description 12
- 239000000839 emulsion Substances 0.000 description 12
- 235000019698 starch Nutrition 0.000 description 12
- 239000008273 gelatin Substances 0.000 description 11
- 229940014259 gelatin Drugs 0.000 description 11
- 229920000159 gelatin Polymers 0.000 description 11
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 11
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 11
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 11
- 238000000338 in vitro Methods 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- 229920001223 polyethylene glycol Polymers 0.000 description 11
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 11
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 11
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- 108010010803 Gelatin Proteins 0.000 description 10
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 10
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 10
- 230000027455 binding Effects 0.000 description 10
- 235000019322 gelatine Nutrition 0.000 description 10
- 235000011852 gelatine desserts Nutrition 0.000 description 10
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 10
- 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 10
- 239000011159 matrix material Substances 0.000 description 10
- 230000004060 metabolic process Effects 0.000 description 10
- 229920000642 polymer Polymers 0.000 description 10
- 239000003755 preservative agent Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 9
- 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 9
- 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 9
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 9
- 239000005977 Ethylene Substances 0.000 description 9
- 239000001768 carboxy methyl cellulose Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000007891 compressed tablet Substances 0.000 description 9
- 239000003937 drug carrier Substances 0.000 description 9
- 235000011187 glycerol Nutrition 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 239000008101 lactose Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 239000000600 sorbitol Substances 0.000 description 9
- 235000010356 sorbitol Nutrition 0.000 description 9
- 239000008107 starch Substances 0.000 description 9
- 229940032147 starch Drugs 0.000 description 9
- 206010067484 Adverse reaction Diseases 0.000 description 8
- 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 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 8
- 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 8
- 239000002202 Polyethylene glycol Substances 0.000 description 8
- 239000004372 Polyvinyl alcohol Substances 0.000 description 8
- 230000006838 adverse reaction Effects 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 238000007796 conventional method Methods 0.000 description 8
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 8
- 230000002255 enzymatic effect Effects 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 239000000499 gel Substances 0.000 description 8
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 229940127557 pharmaceutical product Drugs 0.000 description 8
- 229920002451 polyvinyl alcohol Polymers 0.000 description 8
- 239000003981 vehicle Substances 0.000 description 8
- 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 7
- 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 7
- 229930195725 Mannitol Natural products 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 229920002125 Sokalan® Polymers 0.000 description 7
- 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 7
- 229930006000 Sucrose Natural products 0.000 description 7
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 7
- 230000002411 adverse Effects 0.000 description 7
- 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 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000000576 coating method Methods 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 239000003995 emulsifying agent Substances 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 239000008297 liquid dosage form Substances 0.000 description 7
- 239000000594 mannitol Substances 0.000 description 7
- 235000010355 mannitol Nutrition 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 239000005720 sucrose Substances 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- 229960004295 valine Drugs 0.000 description 7
- 239000004474 valine Substances 0.000 description 7
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 6
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 6
- 239000004698 Polyethylene Substances 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000003963 antioxidant agent Substances 0.000 description 6
- 235000006708 antioxidants Nutrition 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 239000006071 cream Substances 0.000 description 6
- 229940126534 drug product Drugs 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- 230000036541 health Effects 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 230000003204 osmotic effect Effects 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- 229920000573 polyethylene Polymers 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000009885 systemic effect Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 5
- 102100034330 Chromaffin granule amine transporter Human genes 0.000 description 5
- 108050004812 Dopamine receptor Proteins 0.000 description 5
- 102000015554 Dopamine receptor Human genes 0.000 description 5
- 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 5
- 239000001856 Ethyl cellulose Substances 0.000 description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- 108091006772 SLC18A1 Proteins 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229920001615 Tragacanth Polymers 0.000 description 5
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 239000008186 active pharmaceutical agent Substances 0.000 description 5
- 235000010443 alginic acid Nutrition 0.000 description 5
- 229920000615 alginic acid Polymers 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 238000007906 compression Methods 0.000 description 5
- 230000006835 compression Effects 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 230000003111 delayed effect Effects 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 5
- 239000002270 dispersing agent Substances 0.000 description 5
- 239000000975 dye Substances 0.000 description 5
- 235000019325 ethyl cellulose Nutrition 0.000 description 5
- 229920001249 ethyl cellulose Polymers 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 229920000609 methyl cellulose Polymers 0.000 description 5
- 235000010981 methylcellulose Nutrition 0.000 description 5
- 239000001923 methylcellulose Substances 0.000 description 5
- 229960002900 methylcellulose Drugs 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000002674 ointment Substances 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 238000007911 parenteral administration Methods 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- 239000008299 semisolid dosage form Substances 0.000 description 5
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 5
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- 239000000375 suspending agent Substances 0.000 description 5
- 239000012730 sustained-release form Substances 0.000 description 5
- 239000003765 sweetening agent Substances 0.000 description 5
- 239000006188 syrup Substances 0.000 description 5
- 235000020357 syrup Nutrition 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 239000000080 wetting agent Substances 0.000 description 5
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 4
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 241000416162 Astragalus gummifer Species 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 108010078791 Carrier Proteins Proteins 0.000 description 4
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 4
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 4
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 235000010419 agar Nutrition 0.000 description 4
- 239000004599 antimicrobial Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 235000012343 cottonseed oil Nutrition 0.000 description 4
- 239000002385 cottonseed oil Substances 0.000 description 4
- 239000008121 dextrose Substances 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 229960003638 dopamine Drugs 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000010408 film Substances 0.000 description 4
- 235000019634 flavors Nutrition 0.000 description 4
- 229940093915 gynecological organic acid Drugs 0.000 description 4
- 239000000017 hydrogel Substances 0.000 description 4
- 229920001477 hydrophilic polymer Polymers 0.000 description 4
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 4
- 239000004005 microsphere Substances 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 235000005985 organic acids Nutrition 0.000 description 4
- 239000002357 osmotic agent Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000004584 polyacrylic acid Substances 0.000 description 4
- 229920000139 polyethylene terephthalate Polymers 0.000 description 4
- 239000005020 polyethylene terephthalate Substances 0.000 description 4
- 229920001451 polypropylene glycol Polymers 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000006215 rectal suppository Substances 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000011200 topical administration Methods 0.000 description 4
- 239000006216 vaginal suppository Substances 0.000 description 4
- 239000001993 wax Substances 0.000 description 4
- 229940071104 xylenesulfonate Drugs 0.000 description 4
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 108060003345 Adrenergic Receptor Proteins 0.000 description 3
- 102000017910 Adrenergic receptor Human genes 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- 229920001661 Chitosan Polymers 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 description 3
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 3
- 206010013710 Drug interaction Diseases 0.000 description 3
- 206010015995 Eyelid ptosis Diseases 0.000 description 3
- 229920002907 Guar gum Polymers 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- 102000008092 Norepinephrine Plasma Membrane Transport Proteins Human genes 0.000 description 3
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 description 3
- 239000005062 Polybutadiene Substances 0.000 description 3
- 229920002367 Polyisobutene Polymers 0.000 description 3
- 102000003946 Prolactin Human genes 0.000 description 3
- 108010057464 Prolactin Proteins 0.000 description 3
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 3
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 3
- 102000019208 Serotonin Plasma Membrane Transport Proteins Human genes 0.000 description 3
- 108010012996 Serotonin Plasma Membrane Transport Proteins Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 101710164184 Synaptic vesicular amine transporter Proteins 0.000 description 3
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- 235000012211 aluminium silicate Nutrition 0.000 description 3
- 239000000164 antipsychotic agent Substances 0.000 description 3
- 239000008135 aqueous vehicle Substances 0.000 description 3
- 239000003693 atypical antipsychotic agent Substances 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 229960004365 benzoic acid Drugs 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 229960004106 citric acid Drugs 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 239000008139 complexing agent Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000004205 dimethyl polysiloxane Substances 0.000 description 3
- 238000007908 dry granulation Methods 0.000 description 3
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 235000010417 guar gum Nutrition 0.000 description 3
- 239000000665 guar gum Substances 0.000 description 3
- 229960002154 guar gum Drugs 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 238000005805 hydroxylation reaction Methods 0.000 description 3
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 3
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 3
- 229960000367 inositol Drugs 0.000 description 3
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- 238000009533 lab test Methods 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000003589 local anesthetic agent Substances 0.000 description 3
- 229960005015 local anesthetics Drugs 0.000 description 3
- 239000007937 lozenge Substances 0.000 description 3
- 230000037353 metabolic pathway Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000693 micelle Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 3
- 229960003793 midazolam Drugs 0.000 description 3
- 239000002687 nonaqueous vehicle Substances 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 235000019271 petrolatum Nutrition 0.000 description 3
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 3
- 229920002857 polybutadiene Polymers 0.000 description 3
- 229920000098 polyolefin Polymers 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 229920002689 polyvinyl acetate Polymers 0.000 description 3
- 239000011118 polyvinyl acetate Substances 0.000 description 3
- 229920000915 polyvinyl chloride Polymers 0.000 description 3
- 239000004800 polyvinyl chloride Substances 0.000 description 3
- 229940097325 prolactin Drugs 0.000 description 3
- 210000004129 prosencephalon Anatomy 0.000 description 3
- 201000003004 ptosis Diseases 0.000 description 3
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 3
- 229960003147 reserpine Drugs 0.000 description 3
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 3
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 3
- 239000003352 sequestering agent Substances 0.000 description 3
- 229940076279 serotonin Drugs 0.000 description 3
- 229920002379 silicone rubber Polymers 0.000 description 3
- 239000004945 silicone rubber Substances 0.000 description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 3
- 229940001584 sodium metabisulfite Drugs 0.000 description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 description 3
- 235000010199 sorbic acid Nutrition 0.000 description 3
- 239000004334 sorbic acid Substances 0.000 description 3
- 229940075582 sorbic acid Drugs 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- 229910052722 tritium Inorganic materials 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- 239000008136 water-miscible vehicle Substances 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- 229920001285 xanthan gum Polymers 0.000 description 3
- 235000010493 xanthan gum Nutrition 0.000 description 3
- 239000000230 xanthan gum Substances 0.000 description 3
- 229940082509 xanthan gum Drugs 0.000 description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-NJFSPNSNSA-N ((18)O)water Chemical compound [18OH2] XLYOFNOQVPJJNP-NJFSPNSNSA-N 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- FYGDTMLNYKFZSV-URKRLVJHSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](OC2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-URKRLVJHSA-N 0.000 description 2
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 2
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 description 2
- 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 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 2
- OEPOKWHJYJXUGD-UHFFFAOYSA-N 2-(3-phenylmethoxyphenyl)-1,3-thiazole-4-carbaldehyde Chemical compound O=CC1=CSC(C=2C=C(OCC=3C=CC=CC=3)C=CC=2)=N1 OEPOKWHJYJXUGD-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-OUBTZVSYSA-N Ammonia-15N Chemical compound [15NH3] QGZKDVFQNNGYKY-OUBTZVSYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229920002498 Beta-glucan Polymers 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- 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 2
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-IGMARMGPSA-N Carbon-12 Chemical compound [12C] OKTJSMMVPCPJKN-IGMARMGPSA-N 0.000 description 2
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- DQEFEBPAPFSJLV-UHFFFAOYSA-N Cellulose propionate Chemical compound CCC(=O)OCC1OC(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C1OC1C(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C(COC(=O)CC)O1 DQEFEBPAPFSJLV-UHFFFAOYSA-N 0.000 description 2
- 239000004709 Chlorinated polyethylene Substances 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 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 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- 101150049660 DRD2 gene Proteins 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 208000012661 Dyskinesia Diseases 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 2
- 229920000896 Ethulose Polymers 0.000 description 2
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 239000001116 FEMA 4028 Substances 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 244000043261 Hevea brasiliensis Species 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-AHCXROLUSA-N Iodine-123 Chemical compound [123I] ZCYVEMRRCGMTRW-AHCXROLUSA-N 0.000 description 2
- 108090000862 Ion Channels Proteins 0.000 description 2
- 102000004310 Ion Channels Human genes 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 229920000161 Locust bean gum Polymers 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-BJUDXGSMSA-N Nitrogen-13 Chemical compound [13N] QJGQUHMNIGDVPM-BJUDXGSMSA-N 0.000 description 2
- 239000004677 Nylon Substances 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 239000004264 Petrolatum Substances 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 239000008156 Ringer's lactate solution Substances 0.000 description 2
- 229920001800 Shellac Polymers 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- NINIDFKCEFEMDL-NJFSPNSNSA-N Sulfur-34 Chemical compound [34S] NINIDFKCEFEMDL-NJFSPNSNSA-N 0.000 description 2
- NINIDFKCEFEMDL-RNFDNDRNSA-N Sulfur-36 Chemical compound [36S] NINIDFKCEFEMDL-RNFDNDRNSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 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 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000003281 allosteric effect Effects 0.000 description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000000305 astragalus gummifer gum Substances 0.000 description 2
- 229940127236 atypical antipsychotics Drugs 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229920005549 butyl rubber Polymers 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 235000010410 calcium alginate Nutrition 0.000 description 2
- 239000000648 calcium alginate Substances 0.000 description 2
- 229960002681 calcium alginate Drugs 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 2
- BMLSTPRTEKLIPM-UHFFFAOYSA-I calcium;potassium;disodium;hydrogen carbonate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].OC([O-])=O BMLSTPRTEKLIPM-UHFFFAOYSA-I 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- OKTJSMMVPCPJKN-BJUDXGSMSA-N carbon-11 Chemical compound [11C] OKTJSMMVPCPJKN-BJUDXGSMSA-N 0.000 description 2
- 229920003064 carboxyethyl cellulose Polymers 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 229920001727 cellulose butyrate Polymers 0.000 description 2
- 229920006218 cellulose propionate Polymers 0.000 description 2
- WZNRVWBKYDHTKI-UHFFFAOYSA-N cellulose, acetate 1,2,4-benzenetricarboxylate Chemical compound OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.OC(=O)C1=CC(C(=O)O)=CC=C1C(=O)OCC1C(OC2C(C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(COC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)O2)OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)O1 WZNRVWBKYDHTKI-UHFFFAOYSA-N 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 229960004170 clozapine Drugs 0.000 description 2
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000002285 corn oil Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229960000913 crospovidone Drugs 0.000 description 2
- 239000002577 cryoprotective agent Substances 0.000 description 2
- 229930182912 cyclosporin Natural products 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000007907 direct compression Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000003291 dopaminomimetic effect Effects 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 230000008406 drug-drug interaction Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000002662 enteric coated tablet Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 229920005558 epichlorohydrin rubber Polymers 0.000 description 2
- 229960003276 erythromycin Drugs 0.000 description 2
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 2
- 239000005038 ethylene vinyl acetate Substances 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000013265 extended release Methods 0.000 description 2
- 238000013213 extrapolation Methods 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 239000003979 granulating agent Substances 0.000 description 2
- 235000019314 gum ghatti Nutrition 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 235000011167 hydrochloric acid Nutrition 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 229920000554 ionomer Polymers 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 238000010902 jet-milling Methods 0.000 description 2
- 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 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 235000010420 locust bean gum Nutrition 0.000 description 2
- 239000000711 locust bean gum Substances 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 229920003087 methylethyl cellulose Polymers 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 230000017311 musculoskeletal movement, spinal reflex action Effects 0.000 description 2
- 229920003052 natural elastomer Polymers 0.000 description 2
- 229920001194 natural rubber Polymers 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 2
- 229960001597 nifedipine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 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
- 230000004783 oxidative metabolism Effects 0.000 description 2
- QVGXLLKOCUKJST-BJUDXGSMSA-N oxygen-15 atom Chemical compound [15O] QVGXLLKOCUKJST-BJUDXGSMSA-N 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 239000001814 pectin Substances 0.000 description 2
- 229920001277 pectin Polymers 0.000 description 2
- 235000010987 pectin Nutrition 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 229940066842 petrolatum Drugs 0.000 description 2
- ZQBAKBUEJOMQEX-UHFFFAOYSA-N phenyl salicylate Chemical compound OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 ZQBAKBUEJOMQEX-UHFFFAOYSA-N 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 229920001490 poly(butyl methacrylate) polymer Polymers 0.000 description 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 2
- 229920002492 poly(sulfone) Polymers 0.000 description 2
- 229920000570 polyether Polymers 0.000 description 2
- 229920006393 polyether sulfone Polymers 0.000 description 2
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 2
- 229920001195 polyisoprene Polymers 0.000 description 2
- 239000004926 polymethyl methacrylate Substances 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000004804 polysaccharides Chemical class 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 229920001290 polyvinyl ester Polymers 0.000 description 2
- 229920001289 polyvinyl ether Polymers 0.000 description 2
- 229920001291 polyvinyl halide Polymers 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 230000003518 presynaptic effect Effects 0.000 description 2
- 229930010796 primary metabolite Natural products 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 238000003653 radioligand binding assay Methods 0.000 description 2
- 229940081974 saccharin Drugs 0.000 description 2
- 235000019204 saccharin Nutrition 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 239000004208 shellac Substances 0.000 description 2
- 229940113147 shellac Drugs 0.000 description 2
- 235000013874 shellac Nutrition 0.000 description 2
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000002195 soluble material Substances 0.000 description 2
- 235000012424 soybean oil Nutrition 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000007940 sugar coated tablet Substances 0.000 description 2
- 238000009495 sugar coating Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 210000002504 synaptic vesicle Anatomy 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 229920001897 terpolymer Polymers 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- 229960005333 tetrabenazine Drugs 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 208000016686 tic disease Diseases 0.000 description 2
- 239000012049 topical pharmaceutical composition Substances 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 2
- 229960003386 triazolam Drugs 0.000 description 2
- 229940117013 triethanolamine oleate Drugs 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- XLYOFNOQVPJJNP-OUBTZVSYSA-N water-17o Chemical compound [17OH2] XLYOFNOQVPJJNP-OUBTZVSYSA-N 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- NEPLBHLFDJOJGP-BYPYZUCNSA-N (2s)-2-(5-fluoro-2,4-dinitroanilino)propanamide Chemical compound NC(=O)[C@H](C)NC1=CC(F)=C([N+]([O-])=O)C=C1[N+]([O-])=O NEPLBHLFDJOJGP-BYPYZUCNSA-N 0.000 description 1
- XMQUEQJCYRFIQS-YFKPBYRVSA-N (2s)-2-amino-5-ethoxy-5-oxopentanoic acid Chemical compound CCOC(=O)CC[C@H](N)C(O)=O XMQUEQJCYRFIQS-YFKPBYRVSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 description 1
- VSWBSWWIRNCQIJ-GJZGRUSLSA-N (R,R)-asenapine Chemical compound O1C2=CC=CC=C2[C@@H]2CN(C)C[C@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-GJZGRUSLSA-N 0.000 description 1
- BGRJTUBHPOOWDU-NSHDSACASA-N (S)-(-)-sulpiride Chemical compound CCN1CCC[C@H]1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-NSHDSACASA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 1
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 1
- WGIMXKDCVCTHGW-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOCCO WGIMXKDCVCTHGW-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- FEBUJFMRSBAMES-UHFFFAOYSA-N 2-[(2-{[3,5-dihydroxy-2-(hydroxymethyl)-6-phosphanyloxan-4-yl]oxy}-3,5-dihydroxy-6-({[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}methyl)oxan-4-yl)oxy]-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl phosphinite Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(OC2C(C(OP)C(O)C(CO)O2)O)C(O)C(OC2C(C(CO)OC(P)C2O)O)O1 FEBUJFMRSBAMES-UHFFFAOYSA-N 0.000 description 1
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 1
- JRMAQQQTXDJDNC-UHFFFAOYSA-M 2-ethoxy-2-oxoacetate Chemical compound CCOC(=O)C([O-])=O JRMAQQQTXDJDNC-UHFFFAOYSA-M 0.000 description 1
- WROUWQQRXUBECT-UHFFFAOYSA-N 2-ethylacrylic acid Chemical compound CCC(=C)C(O)=O WROUWQQRXUBECT-UHFFFAOYSA-N 0.000 description 1
- ROGIWVXWXZRRMZ-UHFFFAOYSA-N 2-methylbuta-1,3-diene;styrene Chemical compound CC(=C)C=C.C=CC1=CC=CC=C1 ROGIWVXWXZRRMZ-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- SSONCJTVDRSLNK-UHFFFAOYSA-N 2-methylprop-2-enoic acid;hydrochloride Chemical compound Cl.CC(=C)C(O)=O SSONCJTVDRSLNK-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- ODJQKYXPKWQWNK-UHFFFAOYSA-N 3,3'-Thiobispropanoic acid Chemical compound OC(=O)CCSCCC(O)=O ODJQKYXPKWQWNK-UHFFFAOYSA-N 0.000 description 1
- MJKVTPMWOKAVMS-UHFFFAOYSA-N 3-hydroxy-1-benzopyran-2-one Chemical class C1=CC=C2OC(=O)C(O)=CC2=C1 MJKVTPMWOKAVMS-UHFFFAOYSA-N 0.000 description 1
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 description 1
- NZAQRZWBQUIBSF-UHFFFAOYSA-N 4-(4-sulfobutoxy)butane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCCOCCCCS(O)(=O)=O NZAQRZWBQUIBSF-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 244000106483 Anogeissus latifolia Species 0.000 description 1
- 235000011514 Anogeissus latifolia Nutrition 0.000 description 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 101150022946 CYP3 gene Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- BCZXFFBUYPCTSJ-UHFFFAOYSA-L Calcium propionate Chemical compound [Ca+2].CCC([O-])=O.CCC([O-])=O BCZXFFBUYPCTSJ-UHFFFAOYSA-L 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920001747 Cellulose diacetate Polymers 0.000 description 1
- 229920002284 Cellulose triacetate Polymers 0.000 description 1
- 241001227713 Chiron Species 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 241000206575 Chondrus crispus Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010001237 Cytochrome P-450 CYP2D6 Proteins 0.000 description 1
- 208000009011 Cytochrome P-450 CYP3A Inhibitors Diseases 0.000 description 1
- 102100021704 Cytochrome P450 2D6 Human genes 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- MQJKPEGWNLWLTK-UHFFFAOYSA-N Dapsone Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 MQJKPEGWNLWLTK-UHFFFAOYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 101100137368 Dictyostelium discoideum cypD gene Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical group C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Natural products OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 239000001922 Gum ghatti Substances 0.000 description 1
- 229920000569 Gum karaya Polymers 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 101000985296 Homo sapiens Neuron-specific calcium-binding protein hippocalcin Proteins 0.000 description 1
- 101001047090 Homo sapiens Potassium voltage-gated channel subfamily H member 2 Proteins 0.000 description 1
- 101100209984 Homo sapiens SLC18A1 gene Proteins 0.000 description 1
- 101000641239 Homo sapiens Synaptic vesicular amine transporter Proteins 0.000 description 1
- 101000935117 Homo sapiens Voltage-dependent P/Q-type calcium channel subunit alpha-1A Proteins 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- 206010020651 Hyperkinesia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000015592 Involuntary movements Diseases 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 150000008554 L-valines Chemical class 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 241000218652 Larix Species 0.000 description 1
- 235000005590 Larix decidua Nutrition 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 241000195947 Lycopodium Species 0.000 description 1
- 241000195954 Lycopodium clavatum Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- KLPWJLBORRMFGK-UHFFFAOYSA-N Molindone Chemical compound O=C1C=2C(CC)=C(C)NC=2CCC1CN1CCOCC1 KLPWJLBORRMFGK-UHFFFAOYSA-N 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 208000019430 Motor disease Diseases 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical compound C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- RZPAKFUAFGMUPI-UHFFFAOYSA-N Oleandomycin Natural products O1C(C)C(O)C(OC)CC1OC1C(C)C(=O)OC(C)C(C)C(O)C(C)C(=O)C2(OC2)CC(C)C(OC2C(C(CC(C)O2)N(C)C)O)C1C RZPAKFUAFGMUPI-UHFFFAOYSA-N 0.000 description 1
- 239000004104 Oleandomycin Substances 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 101150053185 P450 gene Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 101150009380 PPIF gene Proteins 0.000 description 1
- 102100034943 Peptidyl-prolyl cis-trans isomerase F, mitochondrial Human genes 0.000 description 1
- RGCVKNLCSQQDEP-UHFFFAOYSA-N Perphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 RGCVKNLCSQQDEP-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-OUBTZVSYSA-N Phosphorus-32 Chemical compound [32P] OAICVXFJPJFONN-OUBTZVSYSA-N 0.000 description 1
- OAICVXFJPJFONN-NJFSPNSNSA-N Phosphorus-33 Chemical compound [33P] OAICVXFJPJFONN-NJFSPNSNSA-N 0.000 description 1
- 244000134552 Plantago ovata Species 0.000 description 1
- 235000003421 Plantago ovata Nutrition 0.000 description 1
- 229920012485 Plasticized Polyvinyl chloride Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920000148 Polycarbophil calcium Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 102100022807 Potassium voltage-gated channel subfamily H member 2 Human genes 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 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
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 239000009223 Psyllium Substances 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- 101100209990 Rattus norvegicus Slc18a2 gene Proteins 0.000 description 1
- MXVSRNGVOQIOQU-UHFFFAOYSA-N S(=O)(=O)(O)O.OC(C(=O)OCC(O)CO)CCCCCCCCCCCCCCCC Chemical compound S(=O)(=O)(O)O.OC(C(=O)OCC(O)CO)CCCCCCCCCCCCCCCC MXVSRNGVOQIOQU-UHFFFAOYSA-N 0.000 description 1
- 101100222691 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CPR3 gene Proteins 0.000 description 1
- 101100276454 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYC7 gene Proteins 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 229920002305 Schizophyllan Polymers 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- NINIDFKCEFEMDL-AKLPVKDBSA-N Sulfur-35 Chemical compound [35S] NINIDFKCEFEMDL-AKLPVKDBSA-N 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 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 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 239000003490 Thiodipropionic acid Substances 0.000 description 1
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 102100025330 Voltage-dependent P/Q-type calcium channel subunit alpha-1A Human genes 0.000 description 1
- 206010048010 Withdrawal syndrome Diseases 0.000 description 1
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 1
- FJWGYAHXMCUOOM-QHOUIDNNSA-N [(2s,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6s)-4,5-dinitrooxy-2-(nitrooxymethyl)-6-[(2r,3r,4s,5r,6s)-4,5,6-trinitrooxy-2-(nitrooxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-3,5-dinitrooxy-6-(nitrooxymethyl)oxan-4-yl] nitrate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](O[N+]([O-])=O)[C@H]1O[N+]([O-])=O)O[C@H]1[C@@H]([C@@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)[C@@H](CO[N+]([O-])=O)O1)O[N+]([O-])=O)CO[N+](=O)[O-])[C@@H]1[C@@H](CO[N+]([O-])=O)O[C@@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)[C@H]1O[N+]([O-])=O FJWGYAHXMCUOOM-QHOUIDNNSA-N 0.000 description 1
- PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- KRHYYFGTRYWZRS-BJUDXGSMSA-N ac1l2y5h Chemical compound [18FH] KRHYYFGTRYWZRS-BJUDXGSMSA-N 0.000 description 1
- RWSOTUBLDIXVET-IGMARMGPSA-N ac1l2y5t Chemical compound [32SH2] RWSOTUBLDIXVET-IGMARMGPSA-N 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 229960000250 adipic acid Drugs 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229960001391 alfentanil Drugs 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 150000007824 aliphatic compounds Chemical class 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910000323 aluminium silicate Inorganic materials 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 229940031955 anhydrous lanolin Drugs 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 239000000420 anogeissus latifolia wall. gum Substances 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 229960005245 asenapine Drugs 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- FACXGONDLDSNOE-UHFFFAOYSA-N buta-1,3-diene;styrene Chemical compound C=CC=C.C=CC1=CC=CC=C1.C=CC1=CC=CC=C1 FACXGONDLDSNOE-UHFFFAOYSA-N 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- QDHFHIQKOVNCNC-UHFFFAOYSA-N butane-1-sulfonic acid Chemical compound CCCCS(O)(=O)=O QDHFHIQKOVNCNC-UHFFFAOYSA-N 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 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
- 239000004202 carbamide Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000007073 chemical hydrolysis Effects 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 229960000860 dapsone Drugs 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940096516 dextrates Drugs 0.000 description 1
- 239000008355 dextrose injection Substances 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
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- PSHRANCNVXNITH-UHFFFAOYSA-N dimethylamino acetate Chemical compound CN(C)OC(C)=O PSHRANCNVXNITH-UHFFFAOYSA-N 0.000 description 1
- 238000003618 dip coating Methods 0.000 description 1
- 239000012990 dithiocarbamate Substances 0.000 description 1
- 150000004659 dithiocarbamates Chemical class 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 208000004206 drug-induced akathisia Diseases 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000007911 effervescent powder Substances 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 238000005530 etching Methods 0.000 description 1
- HQQADJVZYDDRJT-UHFFFAOYSA-N ethene;prop-1-ene Chemical group C=C.CC=C HQQADJVZYDDRJT-UHFFFAOYSA-N 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
- 238000011156 evaluation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229960002690 fluphenazine Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 230000001408 fungistatic effect Effects 0.000 description 1
- 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 1
- 239000007789 gas Substances 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 102000054928 human CYP3A Human genes 0.000 description 1
- 108700021672 human CYP3A Proteins 0.000 description 1
- 102000045553 human SLC18A1 Human genes 0.000 description 1
- 102000045572 human SLC18A2 Human genes 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000000416 hydrocolloid Substances 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000008173 hydrogenated soybean oil Substances 0.000 description 1
- 239000008311 hydrophilic ointment Substances 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 229960004337 hydroquinone Drugs 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 229960003162 iloperidone Drugs 0.000 description 1
- XMXHEBAFVSFQEX-UHFFFAOYSA-N iloperidone Chemical compound COC1=CC(C(C)=O)=CC=C1OCCCN1CCC(C=2C3=CC=C(F)C=C3ON=2)CC1 XMXHEBAFVSFQEX-UHFFFAOYSA-N 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007916 intrasternal administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000007915 intraurethral administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- XMBWDFGMSWQBCA-NJFSPNSNSA-N iodane Chemical compound [129IH] XMBWDFGMSWQBCA-NJFSPNSNSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 235000010494 karaya gum Nutrition 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229960004873 levomenthol Drugs 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 229940059904 light mineral oil Drugs 0.000 description 1
- INHCSSUBVCNVSK-UHFFFAOYSA-L lithium sulfate Inorganic materials [Li+].[Li+].[O-]S([O-])(=O)=O INHCSSUBVCNVSK-UHFFFAOYSA-L 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 229960000423 loxapine Drugs 0.000 description 1
- XJGVXQDUIWGIRW-UHFFFAOYSA-N loxapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 XJGVXQDUIWGIRW-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000001055 magnesium Nutrition 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 229960004938 molindone Drugs 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 235000019645 odor Nutrition 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- RZPAKFUAFGMUPI-KGIGTXTPSA-N oleandomycin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C RZPAKFUAFGMUPI-KGIGTXTPSA-N 0.000 description 1
- 229960002351 oleandomycin Drugs 0.000 description 1
- 235000019367 oleandomycin Nutrition 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 229960001057 paliperidone Drugs 0.000 description 1
- 239000003346 palm kernel oil Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 229960000762 perphenazine Drugs 0.000 description 1
- 229960000969 phenyl salicylate Drugs 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
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229940097886 phosphorus 32 Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960003634 pimozide Drugs 0.000 description 1
- YVUQSNJEYSNKRX-UHFFFAOYSA-N pimozide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC(N2C(NC3=CC=CC=C32)=O)CC1 YVUQSNJEYSNKRX-UHFFFAOYSA-N 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 230000004983 pleiotropic effect Effects 0.000 description 1
- 229960005455 polacrilin Drugs 0.000 description 1
- 229920001084 poly(chloroprene) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229950005134 polycarbophil Drugs 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 229960001309 procaine hydrochloride Drugs 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
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 229940093625 propylene glycol monostearate Drugs 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 229940070687 psyllium Drugs 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 230000000541 pulsatile effect Effects 0.000 description 1
- 229960004431 quetiapine Drugs 0.000 description 1
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012502 risk assessment Methods 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 238000009490 roller compaction Methods 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000003229 sclerosing agent Substances 0.000 description 1
- 229940116353 sebacic acid Drugs 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 235000019613 sensory perceptions of taste Nutrition 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229920000468 styrene butadiene styrene block copolymer Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 description 1
- NINIDFKCEFEMDL-OUBTZVSYSA-N sulfur-33 atom Chemical compound [33S] NINIDFKCEFEMDL-OUBTZVSYSA-N 0.000 description 1
- 229960004940 sulpiride Drugs 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 230000035923 taste sensation Effects 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- RBTVSNLYYIMMKS-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)N1CC(N)C1 RBTVSNLYYIMMKS-UHFFFAOYSA-N 0.000 description 1
- ZUHZGEOKBKGPSW-UHFFFAOYSA-N tetraglyme Chemical compound COCCOCCOCCOCCOC ZUHZGEOKBKGPSW-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 235000019303 thiodipropionic acid Nutrition 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- 230000009974 thixotropic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 229920011532 unplasticized polyvinyl chloride Polymers 0.000 description 1
- 239000006217 urethral suppository Substances 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000009528 vital sign measurement Methods 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
- C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychology (AREA)
- Gastroenterology & Hepatology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Emergency Medicine (AREA)
Abstract
提供了向有需要的患者施用选自缬苯那嗪和(+)‑α‑3‑异丁基‑9,10‑二甲氧基‑1,3,4,6,7,11b‑六氢‑2H‑吡啶并[2,1‑a]异喹啉‑2‑醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂的方法,其中所述患者正在用细胞色素P450 3A4(CYP3A4)强诱导剂进行治疗。
Description
本申请要求2017年1月27日提交的第62/451,605号的美国临时申请的权益,所述美国临时申请出于所有目的通过引用并入本文。
多巴胺能系统的调节异常对几种中枢神经系统(CNS)病症(包括神经及精神疾病和病症)是不可或缺的。这些神经及精神疾病和病症包括多动性运动障碍和诸如精神分裂症和情绪障碍的病况。转运蛋白囊泡单胺转运体-2(VMAT2)在突触前的多巴胺释放中发挥重要作用并且调节从细胞质摄取单胺至突触泡用于储存和释放。
尽管这个领域内已经取得进展,仍需要可用于治疗本文所述的神经及精神疾病和病症以及其他相关疾病或病况的新治疗产品。一种此类物质是缬苯那嗪(valbenazine),其具有以下化学结构:
细胞色素P450酶系统(CYP450)负责药物从活性物质生物转化成可以从身体分泌的无活性代谢物。此外,CYP450对某些药物的代谢可以改变药物的PK特征并且导致那些药物随时间的亚治疗血浆水平。
存在超过1500个分组为家族和亚家族的已知P450序列。细胞色素P450基因超家族由已经基于细胞色素P450的进化关系命名的至少207个基因组成。对于这种命名系统,比较了全部细胞色素P450基因的序列,并且那些共有至少40%同一性的细胞色素P450定义为家族(用CYP后接罗马数字或阿拉伯数字命名,例如,CYP3),并且进一步分成亚家族(用大写字母命名,例如,CYP3A),所述亚家族包含那些依据其推导的氨基酸序列至少55%相关的形式。最后,对每种独立形式的细胞色素P450的基因分配阿拉伯数字(例如,CYP3A4)。
CYP3A同工酶是构成至多60%的总人肝脏微粒体细胞色素P450并且已经在胃和肠的消化道及肝脏中发现的细胞色素P450超家族的成员。CYP3A还已经存在于肾上皮细胞、空肠粘膜和肺中。CYP3A是细胞色素P450超家族中最丰富的亚家族之一。
至少五(5)种形式的CYP存在于人CYP3A亚家族中,并且这些形式负责代谢许多结构上多样的药物。在未诱导的个体中,CYP3A可以构成肝脏中15%的P450酶;在肠细胞中,CYP3A亚家族的成员构成超过70%含有CYP的酶。
CYP3A负责代谢多种药物,包括硝苯地平、大环内酯类(macrofide)抗生素(包括红霉素和醋竹桃霉素)、环孢霉素、FK506、特非那丁、他莫昔芬、利多卡因、咪达唑仑、三唑仑、氨苯砜、地尔硫卓、洛伐他汀、奎尼丁、乙基雌二醇、睾酮和阿芬太尼。CYP3A涉及红霉素N去甲基化、环孢菌素氧化、硝苯地平氧化、咪达唑仑羟基化、睾酮6-β-羟基化和皮质醇6-β-羟基化。还已经显示CYP3A在体外参与几种致癌物的生物激活途径和解毒途径。
对以下方法存在明显的、未满足的需求,所述方法向有需要的患者施用VMAT2抑制剂(如缬苯那嗪或(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇)或其药物可接受的盐和/或同位素变体,其中所述患者还正接受可能与VMAT2抑制剂相互作用的另一种物质(例如CYP3A4抑制剂)治疗。本公开内容满足了这些需求和其他需求,如参考以下公开内容显而易见。
简述
提供向有需要的患者施用选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂的方法,所述方法包括:向患者施用治疗有效量的VMAT2抑制剂,并且告知患者或医护工作者,不建议共同施用细胞色素P450 3A4(CYP3A4)强诱导剂。
还提供向有需要的患者施用选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂的方法,其中患者正在接受细胞色素P450 3A4(CYP3A4)强诱导剂治疗,所述方法包括:停止CYP3A4诱导剂治疗并且随后向患者施用VMAT2强抑制剂,从而避免VMAT2抑制剂与CYP3A4强诱导剂组合使用。
本发明的这些方面和其他方面在参考以下详述是显而易见额。为此,本文中阐述了多种参考文献,它们更详细地描述某些背景信息、程序、化合物和/或组合物,并且从而各自通过引用整体并入本文。
详述
在以下描述中,阐述某些具体细节,以提供对各种实施方案的透彻理解。然而,本领域技术人员将理解,可以在没有这些细节的情况下实践本发明。在其他情况下,没有详细显示或描述熟知的结构以避免不必要地模糊对实施方案的描述。除非上下文另有要求,否则在整个本说明书和随后的权利要求中,词语“包含(comprise)”及其变体例如“包含(comprises)”和“包含(comprising)”解释为开放性、包含性意义,即,解释为“包括但不限于”。另外,在本文中提供的标题仅为了方便并且不解释要求保护的发明的范围或含义。
在整个本说明书中对“一个实施方案”或“实施方案”或“一些实施方案”或“某个实施方案”的提及意指与实施方案有关所描述的具体特征、结构或特性包含在至少一个实施方案中。因此,短语“在一个实施方案中”或“在实施方案中”或“在一些实施方案中”或“在某个实施方案中”在整个本说明书中各种位置的出现并不必然地所有都指相同的实施方案。另外,具体特征、结构或特性可以在一个或多个实施方案中以任何适合的方式组合。
另外,如本说明书和所附权利要求中所用,除非上下文另外清楚地说明,否则单数形式“一(a)”、“一(an)”和“该”包括复数指示物。
如本文所用,“缬苯那嗪”可以称作(2R,3R,11bR)-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-基(S)-2-氨基-3-甲基-丁酸酯;或称作(2R,3R,11bR)-1,3,4,6,7,11b-六氢-9,10-二甲氧基-3-(2-甲基丙基)-2H-苯并[a]喹嗪-2-基L-缬氨酸酯或称作NBI-98854。
如本文所用,“(+)-α–HTBZ”意指作为缬苯那嗪的活性代谢物的化合物,其具有结构:
(+)-α–HTBZ可以称作(2R,3R,11bR)-DHTBZ或称作(+)-α-DHTBZ或称作(+)-α–HTBZ或称作R,R,R-DHTBZ或称作(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇;或称作(2R,3R,11bR)-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或称作NBI-98782。
如本文所用,“NBI-136110”意指作为缬苯那嗪的代谢物的化合物,其具有结构:
如本文所用,“同位素变体”意指在构成这种化合物的一个或多个原子处含有非天然比例的同位素的化合物。在某些实施方案中,化合物的“同位素变体”含有非天然比例的一种或多种同位素,所述同位素包括但不限于氢(1H)、氘(2H)、氚(3H)、碳-11(11C)、碳-12(12C)、碳-13(13C)、碳-14(14C)、氮-13(13N)、氮-14(14N)、氮-15(15N)、氧-14(14O)、氧-15(15O)、氧-16(16O)、氧-17(17O)、氧-18(18O)、氟-17(17F)、氟-18(18F)、磷-31(31P)、磷-32(32P)、磷-33(33P)、硫-32(32S)、硫-33(33S)、硫-34(34S)、硫-35(35S)、硫-36(36S)、氯-35(35Cl)、氯-36(36Cl)、氯-37(37Cl)、溴-79(79Br)、溴-81(81Br)、碘-123(123I)、碘-125(125I)、碘-127(127I)、碘-129(129I)和碘-131(131I)。在某些实施方案中,化合物的“同位素变体”处于稳定形式,即,无放射性。在某些实施方案中,化合物的“同位素变体”含有非天然比例的一种或多种同位素,所述同位素包括但不限于氢(1H)、氘(2H)、碳-12(12C)、碳-13(13C)、氮-14(14N)、氮-15(15N)、氧-16(16O)、氧-17(17O)和氧-18(18O)。在某些实施方案中,化合物的“同位素变体”处于不稳定形式,即,有放射性。在某些实施方案中,化合物的“同位素变体”含有非天然比例的一种或多种同位素,所述同位素包括但不限于氚(3H)、碳-11(11C)、碳-14(14C)、氮-13(13N)、氧-14(14O)和氧-15(15O)。应理解,在如本文提供的化合物中,在根据本领域技术人员判断可行的情况下,作为例子,任何氢可以是2H,或作为例子,任何碳可以是13C,或作为例子,任何氮可以是15N,并且作为例子,任何氧可以是18O。在某些实施方案中,化合物的“同位素变体”含有非天然比例的氘。
关于本文提供的化合物,当特定原子位置命名为具有氘或”D”或“d”时,可以理解,氘在该位置的丰度基本上大于氘的天然丰度,后者为约0.015%。在某些实施方案中,命名为具有氘的位置通常在每个命名的氘位置具有至少1000(掺入15%氘)、至少2000(掺入30%氘)、至少3000(掺入45%氘)、至少3500(掺入52.5%氘)、至少4000(掺入60%氘)、至少4500(掺入67.5%氘)、至少5000(掺入75%氘)、至少5500(掺入82.5%氘)、至少6000(掺入90%氘)、至少6333.3(掺入95%氘)、至少6466.7(掺入97%氘)、至少6600(掺入99%氘)或至少6633.3(掺入99.5%氘)的最小同位素富集因子。可以使用本领域普通技术人员已知的常规分析方法(包括质谱法、核磁共振光谱法和结晶学)测定本文提供的化合物的同位素富集。
如本文所用,当物质可以通过酶作用于该物质被化学转化时,它是酶活性的“底物”。底物可以由酶激活或失活。
“酶活性”广泛地指酶的比活性(即,每mg或摩尔酶的酶转化底物的速率)以及这类转化的代谢作用。
当酶的比活性或其比活性的代谢作用可能因存在某物质而下降时,所述物质是酶活性的“抑制剂”,不涉及此类下降的精确机制。例如,物质可以是通过竞争性、非竞争性、变构或其他类型的酶抑制作用、通过减少酶表达或其他直接或间接机制的酶活性的抑制剂。给定药物与抑制剂的共同施用可以降低所述药物通过所列代谢途径代谢的速率。
当酶的比活性或其比活性的代谢作用可能因存在某物质而升高时,所述物质是酶活性的“诱导物”,不涉及此类升高的精确机制。例如,物质可以是通过增加反应速率、通过增加酶表达、通过变构活化或者其他直接或间接机制的酶活性的诱导物。给定药物与酶诱导物的共同施用可以增加通过所示途径代谢的药物的排泄速率。
在不考虑临床意义的情况下,这些对酶活性的作用中任一种可以在单个样品、供体或患者中在给定的活性剂浓度时出现。某物质可能是酶活性的底物、抑制剂或诱导物。例如,所述物质可以是通过一种机制的酶活性的抑制剂并且是通过另一种机制的酶活性的诱导物。物质(底物、抑制剂或诱导物)相对于酶的活性的功能可以取决于环境条件。
可以例如在http://www.genemedrx.com/Cytochrome_P450_Metabolism_Table.php和其他网址以及http://www.ildcare.eu/downloads/artseninfo/drugs_metabolized_by_cyp450s.pdf中发现CYP3A4的抑制剂、诱导物和底物的列表。
如本文所用,“CYP3A4强诱导剂”是减少CYP3A4途径的敏感指数底物的浓度时间曲线下的面积(AUC)>80%的化合物。指数底物可预测地表现出由于抑制或诱导给定代谢途径所致的暴露量增加并且常用于前瞻性临床药物-药物相互作用研究中。敏感指数底物是在临床药物-药物相互作用研究中给定代谢途径的强的指数抑制剂的情况下表现AUC增加≥5倍的指数底物。CYP3A途径的敏感指数底物的实例是咪达唑仑和三唑仑。参见,例如在https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabel ing/ucm093664.htm的药物开发和药物相互作用:底物、抑制剂和诱导物列表。
如本文所用,“多动性障碍”或“多动性运动障碍”或“运动过度”是指特征为过多异常的非自主运动的病症或疾病。这些神经病症包括震颤、肌张力障碍、肌阵挛、手足多动症、亨廷顿病、迟发性运动障碍、图雷特综合征、肌张力障碍、偏侧投掷症、舞蹈病、老年舞蹈病或抽搐。
如本文所用,“迟发性综合征”涵盖但不限于迟发性运动障碍、迟发性肌张力障碍、迟发性失静症、迟发性抽搐、肌阵挛、震颤和紧急戒断综合征。迟发性运动障碍特征在于面部、四肢或躯干的快速、反复、刻板性非自主运动。
如本文所用,“约”意指规定值的±20%、并且更具体地包括规定值的±10%、±5%、±2%和±1%。
如本文所用,“AUC”是指给药事件后活性药物成分或代谢物的血浆浓度随时间的曲线下的面积或积分。
如本文所用,“AUC0-t”是从时间0(给药)至时间“t”的血浆浓度曲线下的积分。
如本文所用,“AUC0-∞”是从时间0(给药)至时间无限的AUC。除非另外说明,否则AUC是指AUC0-∞。通常,药物以盐形式包装,例如缬苯那嗪二甲苯磺酸盐,并且剂型强度是指这种盐形式的质量或相应游离碱(缬苯那嗪)的等同质量。
如本文所用,“Cmax”是药代动力学参数,其表示递送活性药物成分后最大的观测血浆浓度。Cmax在最高血浆浓度tmax时出现。
如本文所用,“共同施用(co-administer)”和“共同施用(co-administration)”及其变体意指将至少两种药物依次、同时或因此在时间上彼此接近(例如,在同日或同周或相同30天时间段内,或足以接近,从而至少两种药物中的每一种可以在血浆中同时检出)施用于患者。当共同施用时,两种或更多种活性剂可以共同配制为相同组合物的一部分或作为单独的制剂施用。这在本文中也可以称作“同时”施用或其变体。
如本文所用,“调节施用”、“改变施用”、“调节给药”或“改变给药”均是等同的并且意指逐渐减少、减少或增加物质的剂量、停止向患者施用物质或用不同的活性剂替换所述物质。
如本文所用,“向患者施用”是指经由本领域认可的引入手段,将组合物或剂型引入患者的过程。
如本文所用,术语“病症”旨在通常与术语“疾病”、“综合征”和“病况”(如医学病况中)是同义的并且与其互换使用,它们均反映人或动物身体或其部分之一的异常状况,所述异常状况损害正常功能,通常表现为区别性体征和症状。
如本文所用,“剂量”意指由患者一次服用的活性剂的测定量。在某些实施方案中,其中活性剂不是缬苯那嗪游离碱,量为与相应量的缬苯那嗪游离碱等同的摩尔数。例如,药物通常以药物可接受的盐形式包装,例如缬苯那嗪二甲苯磺酸盐,并且剂量强度是指相应游离碱(缬苯那嗪)的摩尔等同物的质量。作为一个例子,73mg的缬苯那嗪甲苯磺酸盐是40mg的缬苯那嗪游离碱的摩尔等同物。
如本文所用,“给药方案”意指患者在第一次服用的活性剂的剂量和由患者服用活性剂的任何后续剂量的间期,所述后续剂量例如约20mg至约160mg每日一次,例如,约20mg、约40mg、约60mg、约80mg、约100mg、约120mg或约160mg每日一次。活性剂的额外剂量可以不同于第一次服用的剂量。
如本文所用,试剂、化合物、组合物或组合的“有效量”和“治疗有效量”是施用于受试者或患者(例如,人受试者或患者)时无毒并有效产生某些所需治疗效果的量。受试者的精确治疗有效量可以取决于例如受试者的体格和健康、病况的性质和程度、选择用于施用的疗法或疗法组合和本领域技术人员已知的其他变量。给定病状的有效量通过常规实验确定并处于临床医生的判断范围内。
如本文所用,“告知”意指提到或提供已公开的材料,例如,向使用者提供活性剂连同公开的材料;或口头陈述信息,例如,通过在学术会议、会议或其他教育演讲时提出、通过药物销售代表与医护工作者之间的谈话或通过医护工作者与患者之间的谈话来提出;或出于理解目的,向使用者展示预期的信息。
如本文所用,“标签”意指关于药物产品或剂型或伴随这类药物产品或剂型的全部标签或其他的书面、印刷、图形、电子、言语或展示性沟通的手段。
如本文所用,“医护工作者”意指可能需要或利用关于活性剂(包括其剂型)的信息(包括关于安全性、功效、给药、施用或药代动力学的信息)的健康保健领域的工作者。医护工作者的实例包括医师、药剂师、医师助手、护士、辅助人员、看护人员(可以包括家庭成员或监护人)、急救医疗工作者和兽医师。
如本文所用,“药物指南”意指FDA批准的针对药物产品的患者标签,其符合在21CFR 208和其他适用法规中所述的规定,所述适用法规含有患者如何安全使用药物产品的信息。药物指南在科学上是准确的并且以依据21CFR 201.57批准的药物产品的专业标签为基础并且不与之冲突,但是语言不必与已批准的标签中与药物指南对应的部分相同。药物指南一般可用于具有特殊风险管理信息的药物产品。
如本文所用,“患者”或“个体”或“受试者”意指需要治疗的哺乳动物(包括人)并且通常是指治疗的接受者。
如本文所用,“患者包装说明书”意指患者如何安全使用药物产品的信息,所述信息是FDA已批准标签的一部分。它是调配产品时可以分配给患者的药物产品的专业标签的扩展,其以外行语言提供关于产品的面向消费者的信息,例如它可以描述益处、风险、如何识别风险、剂量或施用。
如本文所用,“药物可接受的”是指并非在生物上或以其他方式不利的材料,即,可以将材料并入向患者施用的药物组合物中,而不造成任何不利的生物学作用或不以有害方式与组合物中含有的任何其他组分相互作用。当术语“药物可接受的”用于是指药物载体或赋形剂时,暗示载体或辅料已经满足要求的毒理学检验和生产检验的标准,并且暗示它包含在美国食品药品监督管理局编制的非活性成分指南上。如在“药理学活性”(或“活性”)衍生物或类似物中的“药理学活性”(或简单地“活性”)是指具有与母体化合物相同类型药理学活性并且程度上大致等同的衍生物或类似物。术语“药物可接受的盐”包括用无机酸(例如氢氯酸或磷酸)或这类有机酸(例如乙酸、草酸、酒石酸、扁桃酸等)形成的酸加成盐。用游离羧基形成的盐也可以来自无机碱,例如,氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁和这类有机碱如异丙胺、三甲胺、组氨酸、普鲁卡因等。
如本文所用,“产品”或“药物产品”意指活性剂的剂型加公开的材料,以及任选地包装物。
如本文所用,“产品说明书”意指药物产品的专业标签(处方信息)、药物产品的患者药品说明书或药物产品的药物指南。
如本文所用,“专业标签”或“处方信息”意指由监管药物产品销售的监管机构(例如,FDA或EMEA)批准的药物产品的正式说明书,其包括药物的安全和有效使用所需要的必备科学信息的概要,例如,适应症和用法;剂量和施用;谁应服用它;不良事件(副作用);特殊人群(孕妇、儿童、老年人等)的使用说明;面向患者的安全信息等。
如本文所用,“公开的材料”意指提供信息的媒介,包括印刷、音频、视频或电子介质,例如传单、广告、产品说明书、印制标签、互联网网站、互联网网页、互联网弹窗、无线电或电视播出、光盘、DVD、录音或其他记录或电子媒介。
如本文所用,“风险”意指由医学治疗引起的不良反应、损伤或其他不利结果的概率或几率。“可接受的风险”意指由个体或群体耐受的医学治疗引起的伤害、损伤或疾病的风险度量。风险是否“可接受”将取决于个体或群体意识到作为承担风险的回报可获得的优势、他们是否接受无论提供任何关于风险幅度的科学建议和其他建议,以及许多其他的政治和社会因素。不良反应的“可接受风险”意指个体或社会群体愿意承担或经历这样的风险:可能发生不良反应,原因是不良反应是其发生概率小或其后果如此轻微、或活性剂的(感知到或真实的)益处如此巨大的一种反应。不良反应的“不可接受风险”意指当权衡不良反应的发生概率、不良反应的后果和活性剂的(感知到或真实的)益处时,个体或社会群体不愿意承担或经历这样的风险:可能发生不良反应。“面临风险”意指处于特征为高水平风险或敏感性的状态或状况。风险评估由鉴定并表征与产品的使用相关的险风的性质、频率和严重程度组成。
如本文所用,“安全性”意指与施用活性剂相关的不良事件的发生率或严重程度,所述不良事件包括与患者相关因素(例如,年龄、性别、族裔、人种、目标疾病、肾或肝功能的异常、共病(co-morbid illnesses)、诸如代谢状态的遗传特性、或环境)和活性剂相关因素(例如,剂量、血浆水平、暴露持续时间或伴同药物)相关的不良作用。
如本文所用,“tmax”是药代动力学参数,其表示递送活性药物成分后至最大血浆浓度的时间。
如本文所用,“t1/2”或“血浆半衰期”或“消除半衰期”等是药代动力学参数,其表示表观血浆末期半衰期,即,药物吸收和分布完成后血浆浓度降低一半的时间。
如本文所用,“治疗(treating)”或“治疗(treatment)”是指减缓或制止病症进展的治疗性应用、防止病症发展的预防性应用和/或逆转病症。逆转病症不同于减缓或停止病症进展的治疗性应用,不同在于采用逆转方法,不仅完全停止病症进展,而且细胞行为在某种程度上移向缺少病症的情况下将观察到的正常状态。
如本文所用,“VMAT2”是指人囊泡单胺转运体同工型2,一种用于将单胺、尤其是神经递质如多巴胺、去甲肾上腺素、血清素和组胺从细胞胞质溶胶转运入突触泡的整合膜蛋白。
如本文所用,术语“VMAT2抑制剂”、“抑制VMAT2”或“VMAT2的抑制”是指本文公开的化合物改变VMAT2的功能的能力。VMAT2抑制剂可以通过在抑制剂与VMAT2之间形成可逆或不可逆性共价键或通过形成非共价键合的复合物来阻断或降低VMAT2的活性。这种抑制可以仅表现在特定细胞类型中或可以取决于特定的生物学事件。术语“VMAT2抑制剂”、“抑制VMAT2”或“抑制VMAT2”还指通过减少在VMAT2与天然底物之间形成复合物的概率来改变VMAT2的功能。
提供向有需要的患者施用选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂的方法,所述方法包括:向患者施用治疗有效量的VMAT2抑制剂,并且告知患者或医护工作者,不建议共同施用细胞色素P450 3A4(CYP3A4)强诱导剂。
在某些实施方案中,所述方法还包括确定患者是否正在施用CYP3A4强诱导剂。
在某些实施方案中,告知患者或医护工作者,应避免或停止共同施用CYP3A4强诱导剂。
还提供向有需要的患者施用选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂的方法,其中所述患者正在用细胞色素P450 3A4(CYP3A4)强诱导剂进行治疗,所述方法包括:停止CYP3A4强诱导剂治疗并且随后向患者施用VMAT2抑制剂,从而避免VMAT2抑制剂与CYP3A4强诱导剂组合使用。
在某些实施方案中,CYP3A4强诱导剂选自奈韦拉平、戊巴比妥、苯妥英、鲁玛卡托(lumacaftor)、利福布汀、利福平、卡马西平、磷苯妥英、苯巴比妥、扑米酮、扑米酮、恩杂鲁胺、米托坦和贯叶连翘。在某些实施方案中,CYP3A4强诱导剂选自利福平、卡马西平、苯妥英和贯叶连翘(St.John’s Wort)。在某些实施方案中,CYP3A4强诱导剂是利福平。
在某些实施方案中,向患者施用VMAT2抑制剂以治疗神经或精神疾病或病症。
在某些实施方案中,神经或精神疾病或病症是多动性运动障碍、情感障碍、双相障碍、精神分裂症、情感分裂障碍、情感障碍中的躁狂、情感障碍中的抑郁、治疗难治性强迫性障碍、与Lesch-Nyhan综合征相关的神经功能障碍、与阿尔茨海默病相关的躁动、脆性X综合征或脆性X相关的震颤-共济失调综合征、自闭症谱系障碍、Rett综合征或舞蹈病-棘状红细胞增多症。
在某些实施方案中,神经或精神疾病或病症是多动性运动障碍。在某些实施方案中,多动性运动障碍是迟发性运动障碍。在某些实施方案中,多动性运动障碍是图雷特综合征。在某些实施方案中,多动性运动障碍是亨廷顿病。在某些实施方案中,多动性运动障碍是抽搐。在某些实施方案中,多动性运动障碍是与亨廷顿病相关的舞蹈病。在某些实施方案中,多动性运动障碍是共济失调、舞蹈病、肌张力障碍、亨廷顿病、肌阵挛、不宁腿综合征或震颤。
在某些实施方案中,口服施用VMAT2抑制剂。
在某些实施方案中,以片剂或胶囊的形式施用VMAT2抑制剂。
在某些实施方案中,VMAT2抑制剂伴随或不伴随食物施用。
在某些实施方案中,VMAT2抑制剂是缬苯那嗪或其药物可接受的盐和/或同位素变体。在某些实施方案中,VMAT2抑制剂是缬苯那嗪或其药物可接受的盐。在某些实施方案中,VMAT2抑制剂是缬苯那嗪甲苯磺酸盐。在某些实施方案中,VMAT2抑制剂是缬苯那嗪的二甲苯磺酸盐。在某些实施方案中,VMAT2抑制剂是同位素变体,其是(2R,3R,11bR)-1,3,4,6,7,11b-六氢-9,10-二(甲氧基-d3)-3-(2-甲基丙基)-2H-苯并[a]喹嗪-2-基L-缬氨酸酯或其药物可接受的盐。
在某些实施方案中,VMAT2抑制剂是(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体。在某些实施方案中,VMAT2抑制剂是(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐。在某些实施方案中,VMAT2抑制剂是同位素变体,其是(+)-α-3-异丁基-9,10-二(甲氧基-d3)-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐。
在某些实施方案中,VMAT2抑制剂以等同于约20mg至约160mg的缬苯那嗪游离碱的量施用。在某些实施方案中,VMAT2抑制剂以等同于约20mg的缬苯那嗪游离碱的量施用。在某些实施方案中,VMAT2抑制剂以等同于约40mg的缬苯那嗪游离碱的量施用。在某些实施方案中,VMAT2抑制剂以等同于约60mg的缬苯那嗪游离碱的量施用。在某些实施方案中,VMAT2抑制剂以等同于约80mg的缬苯那嗪游离碱的量施用。在某些实施方案中,VMAT2抑制剂以等同于约120mg的缬苯那嗪游离碱的量施用。在某些实施方案中,VMAT2抑制剂以等同于约160mg的缬苯那嗪游离碱的量施用。
在某些实施方案中,VMAT2抑制剂以第一量施用第一时间段并且随后将量增加至第二量。在某些实施方案中,第一时间段是一周。在某些实施方案中,第一量等同于约40mg的缬苯那嗪游离碱。在某些实施方案中,第二量等同于约80mg的缬苯那嗪游离碱。
在某些实施方案中,以足以在8小时的时间内实现每mL血浆约15ng至约60ng的(+)-α-DHTBZ的最大血浆浓度(Cmax)和每mL血浆至少15ng的(+)-α-DHTBZ的最小血浆浓度(Cmin)的量施用VMAT2抑制剂。
在某些实施方案中,以足以在12小时的时间内实现每mL血浆约15ng至约60ng的(+)-α-DHTBZ的最大血浆浓度(Cmax)和大约为Cmax的约至少33%至50%的最小血浆浓度(Cmin)的量施用VMAT2抑制剂。
在某些实施方案中,VMAT2抑制剂以足以在约8小时至约24小时的时间内实现以下的量施用:(i)每mL血浆约15ng至约60ng的(+)-α-DHTBZ的治疗浓度范围;以及(ii)每mL血浆至少15ng的(+)-α-DHTBZ的阈值浓度。
在某些实施方案中,在此提供用于治疗神经或精神疾病或病症的方法,所述方法包括以足以在8小时的时间内实现每mL血浆约15ng至约60ng的R,R,R-DHTBZ的最大血浆浓度(Cmax)和每mL血浆至少15ng的R,R,R-DHTBZ的最小血浆浓度(Cmin)的量,向受试者施用包含VMAT2抑制剂的药物组合物。
在某些实施方案中,R,R,R-DHTBZ的Cmax是约15ng/mL血浆、约20ng/mL血浆、约25ng/mL血浆、约30ng/mL血浆、约35ng/mL血浆、约40ng/mL血浆、约45ng/mL血浆、约50ng/mL血浆、约55ng/mL血浆或约60ng/mL血浆。在某些实施方案中,在8小时、12小时、16小时、20小时、24小时、28小时或32小时的时间内,R,R,R-DHTBZ的Cmin是至少15ng/mL血浆、至少20ng/mL血浆、至少25ng/mL血浆、至少30ng/mL血浆、或至少35ng/mL血浆。在某些实施方案中,R,R,R-DHTBZ的Cmin为约15ng/mL至约35ng/mL。
在某些实施方案中,以足以在24小时的时间内提供每mL血浆约15ng至约60ng的R,R,R-DHTBZ的Cmax和Cmax的约至少33%的Cmin的量施用药物组合物。在某些实施方案中,以足以在24小时的时间内提供每mL血浆约15ng至约60ng的R,R,R-DHTBZ的Cmax和Cmax的约至少50%的Cmin的量施用药物组合物。在某些实施方案中,以足以在24小时的时间内提供每mL血浆约15ng至约60ng的R,R,R-DHTBZ的Cmax和约为Cmax的约至少33%至50%的Cmin的量施用药物组合物。
在某些实施方案中,以足以在12小时的时间内提供每mL血浆约15ng至约60ng的R,R,R-DHTBZ的Cmax和Cmax的约至少33%的Cmin的量施用药物组合物。在某些实施方案中,以足以在12小时的时间内提供每mL血浆约15ng至约60ng的R,R,R-DHTBZ的Cmax和Cmax的约至少50%的Cmin的量施用药物组合物。在某些实施方案中,以足以在12小时的时间内提供每mL血浆约15ng至约60ng的R,R,R-DHTBZ的Cmax和约为Cmax的约至少33%至50%的Cmin的量施用药物组合物。
在某些实施方案中,药物组合物以在24小时的时间内提供每mL血浆约15ng至约60ng的R,R,R-DHTBZ的Cmax和约5ng至约30ng的Cmin的量施用于受试者。在某些实施方案中,药物组合物以在24小时的时间内提供每mL血浆约15ng至约60ng的R,R,R-DHTBZ的Cmax和约7.5ng至约30ng的Cmin的量施用于受试者。
在某些实施方案中,本文提供用于治疗神经或精神疾病或病症的方法,所述方法包括以足以在约8小时至约24小时的时间内提供以下的量向受试者施用包含VMAT2抑制剂作为活性药物成分的药物组合物:(i)每mL血浆约15ng至约60ng的R,R,R-DHTBZ的治疗浓度范围和(ii)每mL血浆至少15ng的R,R,R-DHTBZ的阈值浓度。
在某些实施方案中,治疗浓度范围是约15ng至约35ng、至约40ng、至约45ng、至约50ng或至约55ng R,R,R-DHTBZ/mL血浆。
在某些实施方案中,在约8小时、约12小时、约16小时、约20小时、约24小时、约28小时或约32小时的时间内,R,R,R-DHTBZ的阈值浓度是约15ng/mL血浆、约20ng/mL血浆、约25ng/mL血浆、约30ng/mL血浆、约35ng/mL血浆、约40ng/mL血浆、约45ng/mL血浆、约50ng/mL血浆、约55ng/mL血浆或约60ng/mL血浆。在某些实施方案中,在约8小时至约24小时的时间内,R,R,R-DHTBZ的阈值浓度是约15ng/mL至35ng/mL。
可以通过本领域已知的方法测量血浆浓度并且通常通过串联质谱法测量血浆浓度。
还提供选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂,用于治疗有需要的患者中的神经或精神疾病或病症的方法中,其中事先已经确定患者已经停止CYP3A4强诱导剂的治疗,所述方法包括:向患者施用治疗有效量的VMAT2抑制剂。
还提供选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂,用于治疗有需要的患者中的神经或精神疾病或病症的方法中,所述方法包括:确定患者是否正在施用CYP3A4强诱导剂,选择患者用于治疗,其中患者未正在施用CYP3A4强诱导剂,以及向选择的患者施用治疗有效量的VMAT2抑制剂。
还提供选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂,用于治疗有需要的患者中的神经或精神疾病或病症的方法中,所述方法包括:向患者施用治疗有效量的VMAT2抑制剂,随后确定患者是否正在施用CYP3A4强诱导剂,选择患者用于治疗,其中患者未正在施用CYP3A4强诱导剂,以及向患者施用治疗有效量的VMAT2抑制剂。
可以根据第8,039,627号和第8,357,697号美国专利制备缬苯那嗪,所述美国专利各自的公开内容通过引用整体并入本文。可以通过多种方法施用四苯喹嗪,所述方法包括在PCT公开WO 2010/018408、WO 2011/019956和WO 2014/047167中公开的制剂,所述PCT公开各自的公开内容通过引用整体并入本文。在某些实施方案中,用于本文提供的组合物和方法中的缬苯那嗪是如第15/338,214号美国序列号中公开的多晶型I,其公开内容通过引用整体并入本文。
药物组合物
还提供用于治疗需要选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂的患者的组合物,所述组合物包含治疗有效量的VMAT2抑制剂,其中告知患者或医护工作者,不建议共同施用细胞色素P450 3A4(CYP3A4)强诱导剂。
在某些实施方案中,告知患者或医护工作者应避免或停止共同施用CYP3A4强诱导剂。
还提供用于治疗需要选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂并且正在用细胞色素P450 3A4(CYP3A4)强诱导剂进行治疗的患者的组合物,所述组合物包含VMAT2抑制剂,其中在将组合物施用于患者之前,停止CYP3A4强诱导剂的治疗,从而避免组合物与CYP3A4强诱导剂组合使用。
在某些实施方案中,组合物用于治疗神经或精神疾病或病症。
在某些实施方案中,组合物以等同于VMAT2抑制剂的约20mg至约120mg的缬苯那嗪游离碱的量施用。在某些实施方案中,组合物以等同于约20mg的VMAT2抑制剂的缬苯那嗪游离碱的量施用。在某些实施方案中,组合物以等同于约40mg的VMAT2抑制剂的缬苯那嗪游离碱的量施用。在某些实施方案中,组合物以等同于约80mg的VMAT2抑制剂的缬苯那嗪游离碱的量施用。在某些实施方案中,组合物以等同于约60mg的VMAT2抑制剂的缬苯那嗪游离碱的量施用。在某些实施方案中,组合物以等同于约120mg的VMAT2抑制剂的缬苯那嗪游离碱的量施用。
在某些实施方案中,组合物以VMAT2抑制剂的第一量施用第一时间段并且随后将量增加至第二量。在某些实施方案中,第一时间段是一周。在某些实施方案中,第一量等同于约40mg的缬苯那嗪游离碱。在某些实施方案中,第二量等同于约80mg的缬苯那嗪游离碱。
本文中还提供用于治疗神经或精神疾病或病症的药物组合物,所述药物组合物包含与一种或多种药物可接受的载体或赋形剂组合的VMAT2抑制剂作为活性药物成分。
赋形剂的选择将在很大程度上取决于多种因素,例如特定的施用模式、赋形剂对活性成分的溶解度和稳定性的作用以及剂型的性质。
本文提供的药物组合物可以以单位剂型或多剂型提供。如本文中使用的单位剂型是指适合用于施用于人和动物受试者并如本领域已知地单独包装的物理上离散的单元。每个单位剂量含有预定量的足以产生期望治疗效果的活性成分,以及所需的药用载体或赋形剂。单位剂型的实例包括安瓿、注射器、以及单独包装的片剂和胶囊。单位剂型可以以其部分或多份施用。多剂型是被包装在单个容器中以分离的单位剂型施用的多个相同的单位剂型。多剂型的实例包括小瓶、片剂或胶囊的瓶子、或品脱或加仑的瓶子。
本文提供的药物组合物可以单独施用,或与本文提供的一种或多种其他化合物、一种或多种其他活性成分组合施用。本文提供的药物组合物可以配制成多种用于口服施用、胃肠外施用和局部施用的剂型。所述药物组合物还可以配制为调释剂型,包括延迟释放剂型、延长释放剂型、持久释放剂型、持续释放剂型、脉冲释放剂型、控制释放剂型、加速和快速释放剂型、靶向释放剂型、程序化释放剂型和胃滞留剂型。这些剂型可以根据本领域技术人员已知的常规方法和技术制备。本文提供的药物组合物可以单次施用或以间期多次施用。应理解,精确剂量和治疗的持续时间可以随正在治疗的患者的年龄、重量和状况而变化,并且可以使用已知的试验方案或通过从体内或体外试验或诊断数据外推而经验地确定。进一步理解,对于任何特定个体,应根据个体需要和施用制剂或监督制剂施用的人员的专业判断随时间调整具体剂量方案。
口服施用
本文提供的药物组合物可以以用于口服施用的固体、半固体或液体剂型提供。本文中使用的口服施用还包括口腔含服施用、舌施用和舌下施用。合适的口服剂型包括,但不限于,片剂、胶囊、丸剂、糖锭、锭剂、软锭剂、扁囊剂、小丸、含药口香糖、颗粒剂、整装粉剂、泡腾的或非泡腾的粉剂或颗粒剂、溶液、乳剂、混悬液、溶液、糯米纸囊剂、喷洒剂、酏剂和糖浆剂。除所述活性成分外,所述药物组合物可以含有一种或多种药学上可接受的载体或赋形剂,包括但不限于,粘合剂、填充剂、稀释剂、崩解剂、润湿剂、润滑剂、助流剂、着色剂、染料迁移抑制剂、甜味剂和矫味剂。
粘合剂或制粒剂给片剂赋予粘聚性以确保片剂在压缩后保持完整。合适的粘合剂或制粒剂包括但不限于,淀粉,例如玉米淀粉、马铃薯淀粉和预胶化淀粉(例如,STARCH1500);明胶;糖,诸如蔗糖、葡萄糖、右旋糖、糖蜜和乳糖;天然的和合成的树胶,例如阿拉伯胶、海藻酸、海藻酸盐、鹿角菜提取物、潘瓦尔胶、印度胶、车前皮粘液、羧甲纤维素、甲基纤维素、聚乙烯吡咯烷酮(PVP)、硅酸镁铝、落叶松阿拉伯半聚乳糖、黄蓍胶粉末和瓜尔胶;纤维素,例如乙基纤维素、醋酸纤维素、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC);微晶纤维素,例如AVICEL-PH-101、AVICEL-PH-103、AVICEL RC-581、AVICEL-PH-105(FMC Corp.,Marcus Hook,PA);及其混合物。合适的填充剂包括但不限于:滑石粉、碳酸钙、微晶纤维素、纤维素粉末、葡聚糖结合剂、高岭土、甘露醇、硅酸、山梨醇、淀粉、预胶化淀粉、及其混合物。所述粘合剂或填充剂可以以约50重量%至约99重量%存在于本文提供的药物组合物中。
合适的稀释剂包括但不限于磷酸二钙、硫酸钙、乳糖、山梨醇、蔗糖、肌醇、纤维素、高岭土、甘露醇、氯化钠、干淀粉和糖粉末。某些稀释剂,诸如甘露醇、乳糖、山梨醇、蔗糖和肌醇,当以足够量存在时,可以给某些压缩片剂赋予允许通过咀嚼在口中崩解的特性。这样的压缩片剂可以用作咀嚼片剂。
合适的崩解剂包括但不限于:琼脂;皂粘土;纤维素,例如甲基纤维素和羧甲纤维素;木材制品;天然海绵;阳离子-交换树脂;海藻酸;树胶,例如瓜尔胶和硅酸镁铝HV;柑橘浆;交联的纤维素,例如交联羧甲纤维素;交联的聚合物,例如交聚维酮;交联淀粉;碳酸钙;微晶纤维素,例如淀粉羟乙酸钠;波拉克林钾;淀粉,例如玉米淀粉、马铃薯淀粉、木薯淀粉和预胶化淀粉;粘土;褐藻酸(aligns);及其混合物。在本文提供的药物组合物中的崩解剂的量随制剂的类型而变化,且是本领域普通技术人员可容易识别的。本文提供的药物组合物可以含有约0.5重量%至约15重量%或约1重量%至约5重量%的崩解剂。
合适的润滑剂包括但不限于:硬脂酸钙;硬脂酸镁;矿物油;轻矿物油;甘油;山梨醇;甘露醇;二醇类,例如山嵛酸甘油酯和聚乙二醇(PEG);硬脂酸;月桂基硫酸钠;滑石;氢化植物油,包括花生油、棉籽油、葵花籽油、芝麻油、橄榄油、玉米油和大豆油;硬脂酸锌;油酸乙酯;月桂酸乙酯;琼脂;淀粉;石松粉(lycopodium);二氧化硅或硅胶,例如200(W.R.Grace Co.,Baltimore,MD)和CAB-O-(Cabot Co.of Boston,MA);及其混合物。本文提供的药物组合物可以含有约0.1重量%至约5重量%的润滑剂。合适的助流剂包括胶体二氧化硅、CAB-0-(Cabot Co.of Boston,MA)和无石棉滑石。着色剂包括以下任一种:经批准的、经验证的、水溶性的FD&C染料,和悬浮于氧化铝水合物上的不溶于水的FD&C染料,和色淀及其混合物。色淀是通过将水溶性染料吸附至重金属的水合氧化物从而产生染料的不溶性形式而形成的组合。矫味剂包括从植物(例如水果)提取的天然矫味剂,和产生令人愉快的味道感觉的化合物(例如薄荷和水杨酸甲酯)的合成掺合物。甜味剂包括蔗糖、乳糖、甘露醇、糖浆剂、甘油和人工甜味剂,例如糖精和阿司帕坦。合适的乳化剂包括明胶、阿拉伯胶、黄蓍胶、皂粘土和表面活性剂,例如聚氧乙烯脱水山梨糖醇单油酸酯(20)、聚氧乙烯脱水山梨糖醇单油酸酯80(80)和三乙醇胺油酸酯。助悬剂和分散剂包括羧甲纤维素钠、果胶、黄蓍胶、硅酸镁铝、阿拉伯胶、羧甲基纤维素钠、羟丙基甲基纤维素和聚乙烯吡咯烷酮。防腐剂包括甘油、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、苯甲酸,苯甲酸钠和醇。润湿剂包括丙二醇单硬脂酸酯、脱水山梨糖醇单油酸酯、二乙二醇单月桂酸酯和聚氧乙烯月桂基醚。溶剂包括甘油、山梨醇、乙醇和糖浆。在乳剂中利用的非水性液体的实例包括矿物油和棉籽油。有机酸包括柠檬酸和酒石酸。二氧化碳的来源包括碳酸氢钠和碳酸钠。
应理解,许多载体和赋形剂即使在同一制剂内也可发挥几种功能。可以将本文提供的药物组合物提供为压缩片剂、模印片剂(table triturates)、可咀嚼锭剂、速溶片剂、复压片剂、或肠溶包衣片剂、糖包衣或薄膜包衣片剂。肠溶包衣片剂是用物质包被的压缩片剂,所述物质耐受胃酸的作用但在肠中溶解或崩解,从而保护活性成分免于胃的酸性环境。肠包衣剂包括但不限于脂肪酸、脂肪、水杨酸苯酯、蜡类、紫胶、氨化紫胶和邻苯二甲酸乙酸纤维素。糖包衣片剂是被糖衣包裹的压缩片剂,所述糖衣可有助于掩盖令人不快的味道或气味以及保护片剂免于氧化。薄膜包衣片剂是被水溶性材料的薄层或薄膜覆盖的压缩片剂。薄膜包衣剂包括,但不限于羟乙基纤维素、羧甲纤维素钠、聚乙二醇4000和邻苯二甲酸乙酸纤维素。薄膜包衣赋予与糖包衣相同的一般特征。复压片剂是通过超过一个压缩循环制成的压缩片剂,包括多层片剂、以及压制包衣片剂或干燥包衣片剂。
所述片剂剂型可以从粉末、结晶或颗粒形式的活性成分单独地或与一种或多种本文描述的载体或赋形剂组合地制备,所述载体或赋形剂包括粘合剂、崩解剂、控释聚合物、润滑剂、稀释剂和/或着色剂。矫味剂和甜味剂在咀嚼片剂和锭剂的形成中是特别有用的。
可以将本文提供的药物组合物提供为软胶囊或硬胶囊,其可以从明胶、甲基纤维素、淀粉或藻酸钙制成。也被称作干填充胶囊(DFC)的硬明胶胶囊由两个部分组成,一个部分滑套在另一个部分上,由此完全包封所述活性成分。软弹性胶囊(SEC)是软的球状壳,例如明胶壳,其通过添加甘油、山梨醇或类似的多元醇而塑化。软明胶壳可以含有防腐剂以防止微生物的生长。合适的防腐剂是如本文中所述的那些,包括对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、以及山梨酸。本文提供的液体、半固体和固体剂型可以被封装入胶囊中。合适的液体和半固体剂型包括在碳酸丙烯酯、植物油或甘油三酯中的溶液和混悬液。如本领域技术人员已知的,还可以包被胶囊以改变或保持活性成分的溶解。
本文提供的药物组合物可以以液体和半固体剂型提供,包括乳剂、溶液、混悬液、酏剂和糖浆剂。乳剂是两相系统,其中一种液体以小球形式分散在整个另一种液体中,所述乳剂可以是水包油或油包水。乳剂可以包括药学上可接受的非水性液体或溶剂、乳化剂和防腐剂。悬浮液可以包括药学上可接受的助悬剂和防腐剂。水性醇溶液可以包括药学上可接受的缩醛,例如低级烷基醛的二(低级烷基)缩醛(术语“低级”是指具有1-6个碳原子的烷基),例如,乙醛二乙基缩醛;以及具有一个或多个羟基的水可混溶的溶剂,例如丙二醇和乙醇。酏剂是澄清的、有甜味的和水醇的溶液。糖浆剂是糖(例如,蔗糖)的浓缩水溶液,并还可以含有防腐剂。对于液体剂型,例如,在聚乙二醇中的溶液,可以用足够量的药学上可接受的液体载体(例如,水)稀释,以便方便地测量用于施用。
其他有用的液体和半固体剂型包括但不限于含有本文提供的活性成分、以及二烷基化的单亚烷基二醇或聚亚烷基二醇的那些,所述二烷基化的单亚烷基二醇或聚亚烷基二醇包括1,2-二甲氧基甲烷、二甘醇二甲醚、三甘醇二甲醚、四甘醇二甲醚、聚乙二醇-350-二甲基醚、聚乙二醇-550-二甲基醚、聚乙二醇-750-二甲基醚,其中350、550和750表示所述聚乙二醇的近似平均分子量。这些制剂可以进一步包含一种或多种抗氧化剂,例如丁羟甲苯(BHT)、丁羟茴香醚(BHA)、没食子酸丙酯、维生素E、氢醌、羟基香豆素、乙醇胺、卵磷脂、脑磷脂、抗坏血酸、苹果酸、山梨醇、磷酸、亚硫酸氢盐、偏亚硫酸氢钠、硫代二丙酸及其酯、以及二硫代氨基甲酸酯。
本文提供的用于口服施用的药物组合物还可以以脂质体、胶束、微球或纳米系统的形式提供。
可以将本文提供的药物组合物提供为非泡腾的或泡腾的颗粒和粉末,以重构为液体剂型。用于非泡腾的颗粒或粉末中的药学上可接受的载体和赋形剂可以包括稀释剂、甜味剂和润湿剂。用于泡腾的颗粒或粉末中的药学上可接受的载体和赋形剂可以包括有机酸和二氧化碳来源。
着色剂和矫味剂可以用在所有以上剂型中。可以将本文提供的药物组合物配制为立即释放剂型或调释剂型,包括延迟释放形式、持续释放形式、脉冲释放形式、控制释放形式、靶向释放形式和程序化释放形式。
可以将本文提供的药物组合物与不会损害期望的治疗作用的其他活性成分、或与补充期望的作用的物质(例如抗酸药、质子泵抑制剂和H2-受体拮抗剂)共配制。
可以通过注射、输注或植入胃肠外地施用本文提供的药物组合物,用于局部或全身施用。本文中使用的胃肠外施用包括静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌肉内、滑膜内和皮下施用。
胃肠外施用
可以将本文提供的药物组合物配制成适合用于胃肠外施用的任何剂型,包括溶液、混悬液、乳剂、胶束、脂质体、微球、纳米系统和适合用于在注射前在液体中配成溶液或混悬液的固体形式。根据药物科学领域的技术人员已知的常规方法可以制备这样的剂型。
旨在用于胃肠外施用的药物组合物可以包含一种或多种药学上可接受的载体和赋形剂,包括但不限于,水性媒介物、水可混溶的媒介物、非水性的媒介物、抗微生物生长的抗微生物剂或防腐剂、稳定剂、促溶剂、等渗剂、缓冲剂、抗氧化剂、局部麻醉剂、助悬剂和分散剂、润湿剂或乳化剂、络合剂、掩蔽剂或螯合剂、低温保护剂、冷冻保护剂、增稠剂、pH调节剂和惰性气体。
合适的水性媒介物包括但不限于水、盐水、生理盐水或磷酸盐缓冲盐水(PBS)、氯化钠注射液、林格氏注射液、等渗的右旋糖注射液、无菌水注射液、右旋糖和乳酸盐林格氏注射液。非水性的媒介物包括但不限于植物来源的不挥发性油、蓖麻油、玉米油、棉籽油、橄榄油、花生油、薄荷油、红花油、芝麻油、大豆油、氢化植物油、氢化大豆油、和椰子油的中链甘油三酯、以及棕榈籽油。水可混溶的媒介物包括但不限于乙醇、1,3-丁二醇、液体聚乙二醇(例如,聚乙二醇300和聚乙二醇400)、丙二醇、甘油、N-甲基-2-吡咯烷酮、二甲基乙酰胺和二甲基亚砜。
合适的抗微生物剂或防腐剂包括但不限于苯酚、甲酚、汞制剂、苯甲醇、三氯叔丁醇、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、硫柳汞、苯扎氯铵、苄索氯铵、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯和山梨酸。合适的等渗剂包括但不限于氯化钠、甘油和右旋糖。合适的缓冲剂包括但不限于磷酸盐和柠檬酸盐。合适的抗氧化剂是如本文中所述的那些,包括亚硫酸氢盐和偏亚硫酸氢钠。合适的局部麻醉剂包括但不限于盐酸普鲁卡因。合适的助悬剂和分散剂是如本文中所述的那些,包括羧甲基纤维素钠、羟丙基甲基纤维素和聚乙烯吡咯烷酮。合适的乳化剂包括本文描述的那些,包括聚氧乙烯脱水山梨糖醇单月桂酸酯、聚氧乙烯脱水山梨糖醇单油酸酯80和三乙醇胺油酸酯。合适的掩蔽剂或螯合剂包括但不限于EDTA。合适的pH调节剂包括但不限于氢氧化钠、盐酸、柠檬酸和乳酸。合适的络合剂包括但不限于环糊精,包括α-环糊精、β-环糊精、羟丙基-β-环糊精、磺丁基醚-β-环糊精和磺丁基醚7-β-环糊精(CyDex,Lenexa,KS)。
可以将本文提供的药物组合物配制为用于单剂量或多剂量施用。所述单剂量制剂被包装在安瓿、小瓶或注射器中。所述多剂量胃肠外制剂必须含有抑制细菌或抑制真菌的浓度的抗微生物剂。如本领域已知和实践的,所有胃肠外制剂必须是无菌的。
在某些实施方案中,将所述药物组合物提供为即用型的无菌溶液。在某些实施方案中,将所述药物组合物提供为无菌的干燥的可溶性产品,包括冻干粉剂和皮下片剂,以在使用前用媒介物重构。在某些实施方案中,将所述药物组合物提供为即用型的无菌混悬液。在某些实施方案中,将所述药物组合物提供为无菌的干燥的不溶性产品,以在使用前用媒介物重构。在某些实施方案中,将所述药物组合物提供为即用型的无菌乳剂。
可以将本文提供的药物组合物配制为立即释放剂型或调释剂型,包括延迟释放形式、持续释放形式、脉冲释放形式、控制释放形式、靶向释放形式和程序化释放形式。
可以将所述药物组合物配制为混悬液、固体、半固体或触变液体,用于作为植入贮库施用。在某些实施方案中,将本文提供的药物组合物分散在固体内部基质中,所述固体内部基质被外部聚合物膜包围,所述聚合物膜不溶于体液,但是允许所述药物组合物中的活性成分扩散穿过。
合适的内部基质包括聚甲基丙烯酸甲酯、聚甲基丙烯酸丁酯、塑化或未塑化的聚氯乙烯、塑化的尼龙、塑化的聚对苯二甲酸乙二醇酯、天然橡胶、聚异戊二烯、聚异丁烯、聚丁二烯、聚乙烯、乙烯-乙酸乙烯共聚物、硅橡胶、聚二甲基硅氧烷、有机硅碳酸酯共聚物、亲水聚合物,例如丙烯酸和甲基丙烯酸的酯的水凝胶、胶原、交联聚乙烯醇和交联的部分水解的聚乙酸乙烯酯。
合适的外部聚合物膜包括聚乙烯、聚丙烯、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、乙烯/乙酸乙烯酯共聚物、硅橡胶、聚二甲基硅氧烷、氯丁橡胶、氯化聚乙烯、聚氯乙烯、氯乙烯与乙酸乙烯酯的共聚物、偏二氯乙烯、乙烯和丙烯、离聚物聚对苯二甲酸乙二醇酯、丁基橡胶、表氯环氧丙烷橡胶、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯酯/乙烯醇三元共聚物和乙烯/乙烯氧基乙醇共聚物。
局部施用
可以将本文提供的药物组合物局部地施用至皮肤、开口或粘膜。本文中使用的局部施用包括(真皮内)真皮、结膜、角膜内、眼内、眼部、耳部、透皮、鼻部、阴道、尿道、呼吸道和直肠施用。
可以将本文提供的药物组合物配制为适合用于为局部或全身效应而局部施用的任何剂型,包括乳剂、溶液、混悬液、乳膏剂、凝胶、水凝胶、软膏剂、扑粉、敷料、酏剂、洗剂、混悬液、酊剂、糊剂、泡沫、薄膜、气雾剂、冲洗剂、喷雾剂、栓剂、绷带、真皮贴剂。本文提供的药物组合物的局部制剂还可以包括脂质体、胶束、微球、纳米系统、及其混合物。
适合用于本文提供的局部制剂的药学上可接受的载体和赋形剂包括,但不限于,水性媒介物、水可混溶的媒介物、非水性的媒介物、抗微生物生长的抗微生物剂或防腐剂、稳定剂、促溶剂、等渗剂、缓冲剂、抗氧化剂、局部麻醉剂、助悬剂和分散剂、润湿剂或乳化剂、络合剂、掩蔽剂或螯合剂、穿透促进剂、低温保护剂、冷冻保护剂、增稠剂和惰性气体。
所述药物组合物还可以通过以下方法局部施用:电穿孔、离子透入法、超声透入疗法、超声促渗和显微操作针或无针注射,例如POWDERJECTTM(Chiron Corp.,Emeryville,CA),和BIOJECTTM(Bioject Medical Technologies Inc.,Tualatin,OR)。
本文提供的药物组合物可以以软膏剂、乳膏剂和凝胶剂的形式提供。合适的软膏剂媒介物包括油性或烃基质,包括例如豚脂、苯甲酸豚脂、橄榄油、棉籽油和其他油、白矿脂;可乳化或吸收基质,例如亲水矿脂、羟基硬脂酸甘油硫酸酯和无水羊毛脂;除水基质,例如亲水软膏;水溶性软膏基质,包括不同分子量的聚乙二醇;乳剂基质,油包水(W/O)乳剂或水包油(O/W)乳剂,包括鲸蜡醇、单硬脂酸甘油酯、羊毛脂和硬脂酸。这些媒介物是软化剂,但是通常需要添加抗氧化剂和防腐剂。
合适的乳膏基质可以是水包油或油包水。乳膏媒介物可以是可水洗的、并含有油相、乳化剂和水相。所述油相也被称为“内”相,其通常由矿脂和诸如鲸蜡醇或硬脂醇的脂肪醇构成。尽管非必须地,所述水相经常在体积上超过油相,并且通常含有保湿剂。乳膏制剂中的乳化剂可以是非离子表面活性剂、阴离子表面活性剂、阳离子表面活性剂或两性表面活性剂。
凝胶是半固体混悬型系统。单相凝胶含有基本上均匀地分布在整个液体载体中的有机大分子。合适的胶凝剂包括交联的丙烯酸聚合物,例如卡波姆、羧基聚烯烃、亲水聚合物,例如聚氧化乙烯、聚氧乙烯-聚氧丙烯共聚物和聚乙烯醇;纤维质聚合物,例如羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、邻苯二甲酸羟丙基甲基纤维素和甲基纤维素;树胶,例如黄蓍胶和黄原胶;海藻酸钠;以及明胶。为了制备均匀的凝胶,可以加入诸如醇或甘油的分散剂,或可以通过研磨、机械混合和/或搅拌来分散胶凝剂。
本文提供的药物组合物可以以栓剂、子宫托、杆剂、敷剂或泥敷剂、糊剂、粉剂、敷料、乳膏剂、硬膏剂、避孕药、软膏剂、溶液、乳剂、混悬液、卫生栓、凝胶、泡沫、喷雾剂或灌肠剂的形式直肠地、尿道地、阴道地或在阴道周围施用。可以使用常规方法制备这些剂型。
直肠、尿道和阴道栓剂是用于插入身体开口的固体,其在常温下为固体,但是在体温下熔化或软化以在开口内释放活性成分。在直肠和阴道栓剂中利用的药学上可接受的载体包括媒介物(例如硬化剂),当其与本文提供的药物组合物配制时产生在体温附近的熔点;以及如本文中所述的抗氧化剂,包括亚硫酸氢盐和偏亚硫酸氢钠。合适的媒介物包括、但不限于,可可脂(可可豆油)、甘油-明胶、碳蜡(聚氧乙烯二醇)、鲸蜡、石蜡、白蜡和黄蜡、以及脂肪酸的单、二和三甘油酯的适当混合物、水凝胶,例如聚乙烯醇、甲基丙烯酸羟乙基酯、聚丙烯酸;甘油化的明胶。可以使用多种媒介物的组合。通过压缩方法或模塑可以制备直肠的和阴道栓剂。直肠和阴道栓剂的典型重量是约2g至3g。
本文提供的药物组合物可以以溶液、混悬液、软膏剂、乳剂、形成凝胶的溶液、溶液用粉末、凝胶、眼部插入物和植入物的形式施用于眼部。
本文提供的药物组合物可以鼻内地或通过吸入至呼吸道施用。所述药物组合物可以以气雾剂或溶液的形式提供,用于使用增压容器、泵、喷雾器、雾化器(例如使用电流体力学产生细雾的雾化器)或喷洒器单独地或与合适的推进剂(例如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷)组合地递送。所述药物组合物还可以提供为用于单独地或与惰性载体(例如乳糖或磷脂)组合地吹入的干粉;以及滴鼻剂。对于鼻内使用,所述粉末可以包含生物粘附剂,包括壳聚糖或环糊精。
可以将用于增压容器、泵、喷雾器、雾化器或喷洒器的溶液或混悬液配制成含有:乙醇,含水乙醇,或用于分散、溶解、或延长本文提供的活性成分的释放的合适的替代试剂,作为溶剂的推进剂;和/或表面活性剂,例如脱水山梨糖醇三油酸酯、油酸或寡乳酸。
本文提供的药物组合物可以微粉化为适合通过吸入递送的大小,例如50微米或更小,或者10微米或更小。使用本领域技术人员已知的粉碎方法,例如螺旋喷射研磨、流化床喷射研磨、形成纳米颗粒的超临界流体加工、高压匀浆化或喷雾干燥,可以制备这样大小的颗粒。
可以将用于吸入器或吹入器的胶囊、泡罩和筒(cartridges)配制成含有以下物质的粉末混合物:本文提供的药物组合物;合适的粉末基质,例如乳糖或淀粉;以及性能调节剂,例如l-亮氨酸、甘露醇或硬脂酸镁。所述乳糖可以是无水的或呈一水合物的形式。其他合适的赋形剂包括葡聚糖、葡萄糖、麦芽糖、山梨醇、木糖醇、果糖、蔗糖和海藻糖。用于吸入/鼻内施用的本文提供的药物组合物可以进一步包含合适的香料,例如薄荷醇和左薄荷脑,或甜味剂,例如糖精或糖精钠。
可以将用于局部施用的本文提供的药物组合物配制成立即释放或调释,包括延迟释放、持续释放、脉冲释放、控制释放、靶向释放和程序化释放。
调释
可以将本文提供的药物组合物配制为调释剂型。本文中使用的术语“调释”表示这样的剂型:其中当通过相同途径施用时,所述活性成分的释放的速率或地方不同于立即释放剂型。调释剂型包括延迟释放、延长释放、持久释放、持续释放、脉动或脉冲释放、控制释放、加速和快速释放、靶向释放、程序化释放和胃滞留剂型。
使用本领域技术人员已知的多种调释装置和方法,包括但不限于,基质控释装置、渗透控释装置、多颗粒控释装置、离子交换树脂、肠溶包衣、多层包衣、微球、脂质体和它们的组合,可以制备呈调释剂型的药物组合物。通过改变所述活性成分的粒度和多态性,也可以改变所述活性成分的释放速率。
使用本领域技术人员已知的基质控释装置可以制造呈调释剂型的本文提供的药物组合物。
在某些实施方案中,使用可侵蚀的基质装置配制呈调释剂型的本文提供的药物组合物,所述可侵蚀的基质装置是水可溶胀的、可蚀解的或可溶性的聚合物,包括合成的聚合物和天然存在的聚合物和衍生物,例如多糖和蛋白。
可用于形成可侵蚀的基质的材料包括、但不限于:甲壳质、壳聚糖、葡聚糖和普鲁兰多糖;琼脂,阿拉伯树胶、刺梧桐树胶、槐豆胶、黄蓍树胶、角叉菜胶、印度树胶、瓜尔胶、黄原胶和硬葡聚糖;淀粉,例如糊精和麦芽糊精;亲水胶体,例如果胶;磷脂,例如卵磷脂;海藻酸盐;丙二醇海藻酸酯;明胶;胶原;以及纤维素材料,例如乙基纤维素(EC)、甲基乙基纤维素(MEC)、羧甲基纤维素(CMC)、CMEC、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、醋酸纤维素(CA)、丙酸纤维素(CP)、丁酸纤维素(CB)、醋酸丁酸纤维素(CAB)、CAP、CAT、羟丙基甲基纤维素(HPMC)、HPMCP、HPMCAS、羟丙基甲基纤维素醋酸偏苯三甲酸酯(HPMCAT)和乙基羟基乙基纤维素(EHEC);聚乙烯吡咯烷酮;聚乙烯醇;聚乙酸乙烯酯;甘油脂肪酸酯;聚丙烯酰胺;聚丙烯酸;乙基丙烯酸或甲基丙烯酸的共聚物(Rohm America,Inc.,Piscataway,NJ);聚(2-羟基乙基-甲基丙烯酸酯);聚丙交酯;L-谷氨酸和L-谷氨酸乙酯的共聚物;可降解的乳酸羟乙酸共聚物;聚-D-(-)-3-羟基丁酸;以及其他丙烯酸衍生物,例如甲基丙烯酸丁酯、甲基丙烯酸甲酯、甲基丙烯酸乙酯、丙烯酸乙酯、甲基丙烯酸(2-二甲基氨基乙基)酯和甲基丙烯酸(三甲基氨基乙基)酯氯化物的同聚物和共聚物。
在某些实施方案中,用不可侵蚀的基质装置配制所述药物组合物。将所述活性成分溶解或分散在惰性基质中,并主要在施用后通过在惰性基质中扩散而释放。适合用作不可侵蚀的基质装置的材料包括、但不限于:不溶性的塑料,例如聚乙烯、聚丙烯、聚异戊二烯、聚异丁烯、聚丁二烯、聚甲基丙烯酸甲酯、聚甲基丙烯酸丁酯、氯化聚乙烯、聚氯乙烯、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、乙烯-醋酸乙烯共聚物、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、氯乙烯与乙酸乙烯酯的共聚物、偏二氯乙烯、乙烯和丙烯、离聚物聚对苯二甲酸乙二醇酯、丁基橡胶、表氯环氧丙烷橡胶、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯酯/乙烯醇三元共聚物和乙烯/乙烯氧基乙醇共聚物、聚氯乙烯、塑化的尼龙、塑化的聚乙烯对苯二甲酸酯、天然橡胶、硅橡胶、聚二甲基硅氧烷、有机硅碳酸酯共聚物,以及;亲水聚合物,例如乙基纤维素、醋酸纤维素、交聚维酮和交联的部分水解的聚乙酸乙烯酯;以及脂肪族化合物,例如巴西棕榈蜡、微晶蜡和甘油三酯。
在基质控释系统中,例如,通过采用的聚合物类型、聚合物粘度、聚合物和/或活性成分的粒度、活性成分相对于聚合物的比率、以及所述组合物中的其他赋形剂,可以控制期望的释放动力学。
通过本领域技术人员已知的方法,包括直接压片、干法或湿法制粒并随后压缩、熔化制粒并随后压缩,可以制备呈调释剂型的本文提供的药物组合物。
使用渗透控释装置可以制造呈调释剂型的本文提供的药物组合物,所述渗透控释装置包括一室系统、两室系统、非对称膜技术(AMT)和挤出核心系统(ECS)。一般而言,这样的装置具有至少两个组件:(a)含有活性成分的核心;以及(b)包封所述核心的具有至少一个递送口的半透膜。所述半透膜控制水从使用的水性环境向所述核心的流入,从而通过穿过所述递送口的挤出造成药物释放。
除所述活性成分以外,所述渗透装置的核心任选地包括渗透剂,所述渗透剂产生从使用环境向所述装置的核心运输水的驱动力。一类渗透剂是水可溶胀的亲水聚合物,其也被称为“渗透聚合物”和“水凝胶”,包括但不限于,亲水的乙烯基和丙烯酸聚合物、诸如藻酸钙的多糖、聚氧化乙烯(PEO)、聚乙二醇(PEG)、聚丙二醇(PPG)、聚(2-羟基乙基甲基丙烯酸酯)、聚丙烯酸、聚甲基丙烯酸、聚乙烯吡咯烷酮(PVP)、交联PVP、聚乙烯醇(PVA)、PVA/PVP共聚物、PVA/PVP与诸如甲基丙烯酸甲酯和乙酸乙烯酯的疏水单体的共聚物、含有大PEO嵌段的亲水聚氨酯、交联羧甲基纤维素钠、角叉菜胶、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素(CMC)和羧基乙基纤维素(CEC)、海藻酸钠、聚卡波非、明胶、黄原胶和淀粉羟乙酸钠。
另一类渗透剂是渗透原(osmogen),其能够吸水以影响跨周围包衣屏障的渗透压梯度。合适的渗透原包括但不限于:无机盐,例如硫酸镁、氯化镁、氯化钙、氯化钠、氯化锂、硫酸钾、磷酸钾、碳酸钠、亚硫酸钠、硫酸锂、氯化钾和硫酸钠;糖,例如右旋糖、果糖、葡萄糖、肌醇、乳糖、麦芽糖、甘露醇、棉子糖、山梨醇、蔗糖、海藻糖和木糖醇;有机酸,例如抗坏血酸、苯甲酸、富马酸、柠檬酸、马来酸、癸二酸、山梨酸、己二酸、依地酸、谷氨酸、对甲基苯磺酸、琥珀酸和酒石酸;脲;及其混合物。
可以采用不同溶出速率的渗透剂来影响最初从所述剂型递送活性成分的速度。例如,诸如Mannogeme EZ(SPI Pharma,Lewes,DE)的无定形糖可以用于在前几小时内提供较快递送以立即产生期望的治疗效果,并在延长的时间段内逐渐地且持续地释放剩余量以维持期望水平的治疗或预防效果。在这种情况下,以这样的速率释放活性成分来替代代谢的和排泄的活性成分的量。
所述核心还可以包括多种如本文中所述的其他赋形剂和载体以增强所述剂型的表现或者促进稳定性或加工。
可用于形成所述半透膜的材料包括各种等级的丙烯酸酯、乙烯基酯、醚、聚酰胺、聚酯和纤维质衍生物,其在生理学上相关的pH下是水可透过的且不溶于水的,或者易于通过化学改变(例如交联)而赋予水不溶性。可用于形成包衣的合适的聚合物的实例包括塑化的、未塑化的和增强的醋酸纤维素(CA)、二乙酸纤维素、三乙酸纤维素、CA丙酸酯、硝酸纤维素、醋酸丁酸纤维素(CAB)、CA氨基甲酸乙酯、CAP、CA氨基甲酸甲酯、CA琥珀酸酯、醋酸纤维素偏苯三甲酸酯(CAT)、CA二甲基氨基乙酸酯、CA碳酸乙酯、CA氯乙酸酯、CA草酸乙酯、CA磺酸甲酯、CA磺酸丁酯、CA对甲苯磺酸酯、乙酸琼脂、直链淀粉三乙酸酯、β葡聚糖乙酸酯、β葡聚糖三乙酸酯、乙醛乙酸二甲酯、槐豆胶的三乙酸酯、水合的乙烯-醋酸乙烯、EC、PEG、PPG、PEG/PPG共聚物、PVP、HEC、HPC、CMC、CMEC、HPMC、HPMCP、HPMCAS、HPMCAT、聚丙烯酸和酯以及聚甲基丙烯酸和酯及其共聚物、淀粉、葡聚糖、糊精、壳聚糖、胶原、明胶、聚烯烃、聚醚、聚砜、聚醚砜、聚苯乙烯、聚卤乙烯、聚乙烯基酯和醚、天然蜡和合成蜡。
半透膜也可以是疏水的多微孔膜,其中所述孔基本上被气体填充且不会被水性介质润湿,但是可透过水,如在第5,798,119号美国专利中所公开的。这样的疏水的、但水透性的膜通常由疏水聚合物例如聚烯烃、聚乙烯、聚丙烯、聚四氟乙烯、聚丙烯酸衍生物、聚醚、聚砜、聚醚砜、聚苯乙烯、聚卤乙烯、聚偏氟乙烯、聚乙烯基酯和醚、天然蜡和合成蜡组成。所述半透膜上的递送口可以在包衣后通过机械或激光打孔形成。还可以通过腐蚀水溶性材料塞或通过使所述膜在所述核心的缺口处的较薄部分破裂而在原位形成递送口。另外,可以在包衣过程中形成递送口。
释放的活性成分的总量和释放速率可以基本上通过所述半透膜的厚度和孔隙率、所述核心的组成、以及所述递送口的数目、大小和位置进行调节。
呈渗透控释剂型的药物组合物可以进一步包含本文所述的另外的常规赋形剂,以促进所述制剂的性能或加工。
根据本领域技术人员已知的常规方法和技术可以制备所述渗透控释剂型。
在某些实施方案中,将本文提供的药物组合物配制为AMT控释剂型,其包含一种非对称渗透膜,所述非对称渗透膜包被包含所述活性成分和其他药学上可接受的赋形剂的核心。根据本领域技术人员已知的常规方法和技术,包括直接压片、干法制粒、湿法制粒和浸渍涂布方法,可以制备所述AMT控释剂型。
在某些实施方案中,将本文提供的药物组合物配制为ESC控释剂型,所述ESC控释剂型包含渗透膜,所述渗透膜包被包含所述活性成分、羟基乙基纤维素和其他药学上可接受的赋形剂的核心。
可以用多颗粒控释装置制造呈调释剂型的本文提供的药物组合物,所述多颗粒控释装置包含大量约10pm至约3mm、约50pm至约2.5mm、或约100pm至1mm直径的微粒、颗粒或小丸。通过本领域技术人员已知的方法,包括湿法制粒和干法制粒、挤出/滚圆、碾压、熔化-凝结、和喷涂种子核心,可以制备这样的多颗粒。
可以将如本文中所述的其他赋形剂与所述药物组合物掺合以辅助加工和形成所述多颗粒。得到的颗粒本身可以构成所述多颗粒装置或者可以用多种薄膜形成材料包被,例如肠溶聚合物、水可溶胀的和水溶性的聚合物。所述多颗粒可以进一步加工为胶囊或片剂。
靶向递送
还可以将本文提供的药物组合物配制成靶向特定的组织、受体或要治疗的受试者的身体的其他区域,包括基于脂质体、基于重新包封的红细胞和基于抗体的递送系统。
剂量
在治疗、预防或改善抽搐病症或与VMAT2抑制有关的其他病况、病症或疾病的一种或多种症状中,适当的剂量水平通常是约0.001至100mg/千克患者体重/天(mg/kg/天)、约0.01至约80mg/kg/天、约0.1至约50mg/kg/天、约0.5至约25mg/kg/天或约1至约20mg/kg/天,所述剂量可以以单剂量或多剂量施用。在此范围内,所述剂量可以是0.005至0.05、0.05至0.5或0.5至5.0、1至15、1至20或1至50mg/kg/天。在某些实施方案中,所述剂量水平是约0.001至100mg/kg/天。
在某些实施方案中,所述剂量水平是约25至100mg/kg/天。在某些实施方案中,所述剂量水平是约0.01至约40mg/kg/天。在某些实施方案中,所述剂量水平是约0.1至约80mg/kg/天。在某些实施方案中,所述剂量水平是约0.1至约50mg/kg/天。在某些实施方案中,所述剂量水平是约0.1至约40mg/kg/天。在某些实施方案中,所述剂量水平是约0.5至约80mg/kg/天。在某些实施方案中,所述剂量水平是约0.5至约40mg/kg/天。在某些实施方案中,所述剂量水平是约0.5至约25mg/kg/天。在某些实施方案中,所述剂量水平是约1至约80mg/kg/天。在某些实施方案中,所述剂量水平是约1至约75mg/kg/天。在某些实施方案中,所述剂量水平是约1至约50mg/kg/天。在某些实施方案中,所述剂量水平是约1至约40mg/kg/天。在某些实施方案中,所述剂量水平是约1至约25mg/kg/天。
在某些实施方案中,所述剂量水平是约5.0至150mg/天,并且在某些实施方案中是10至100mg/天。在某些实施方案中,所述剂量水平是约80mg/天。在某些实施方案中,所述剂量水平是约40mg/天。
对于口服施用,所述药物组合物可以以片剂的形式提供,对于待治疗的患者的剂量的症状判断,所述片剂含有1.0至1,000mg活性成分,特别是约1、约5、约10、约15、约20、约25、约30、约40、约45、约50、约75、约80、约100、约150、约200、约250、约300、约400、约500、约600、约750、约800、约900和约1,000mg活性成分。在某些实施方案中,所述药物组合物可以以含有约100mg活性成分的片剂形式提供。在某些实施方案中,所述药物组合物可以以含有约80mg活性成分的片剂形式提供。在某些实施方案中,所述药物组合物可以以含有约75mg活性成分的片剂形式提供。在某些实施方案中,所述药物组合物可以以含有约50mg活性成分的片剂形式提供。在某些实施方案中,所述药物组合物可以以含有约40mg活性成分的片剂形式提供。在某些实施方案中,所述药物组合物可以以含有约25mg活性成分的片剂形式提供。所述组合物可以以每天1至4次的方案施用,包括每天1次、2次、3次和4次。
然而,应理解,任何特定患者的具体剂量水平和给药频率可以不同,这取决于多种因素,包括所使用的具体化合物的活性、该化合物的代谢稳定性和作用时间长短、年龄、体重、一般健康、性别、饮食、给药方式和时间、排泄速率、药物组合、具体病况的严重性和经受治疗的宿主。
本文提供的化合物还可以与其他药剂组合或组合使用,所述其他药剂可用于治疗、预防或改善本文提供的化合物对其有用的疾病或病况(包括抽搐病症和通常用抗精神病药物治疗的其他病况)的一种或多种症状。
在某些实施方案中,本文提供的化合物还可以与典型的抗精神病药物组合或联合使用。在某些实施方案中,所述典型的抗精神病药物是氟奋乃静、氟哌啶醇、洛沙平、吗茚酮、奋乃静、匹莫齐特、舒必利、甲硫哒嗪或三氟拉嗪。在某些实施方案中,所述抗精神病药物是非典型抗精神病药物。在某些实施方案中,所述非典型抗精神病药物是阿立哌唑,阿塞那平,氯氮平,伊潘立酮,奥氮平,帕潘立酮,喹硫平,利培酮或齐拉西酮。在某些实施方案中,所述非典型抗精神病药物是氯氮平。
此类其他药剂或药物可以与本文提供的化合物同时或依次以其常用途径和用量施用。当本文提供的化合物与一种或多种其他药物同时使用时,可以利用除含有本文提供的化合物以外还含有这样的其他药物的药物组合物,但不要求这样。因此,本文提供的药物组合物包括除含有本文提供的化合物以外还含有一种或多种其他活性成分或治疗剂的药物组合物。
本文提供的化合物与第二种活性成分的重量比可以变化,并取决于每种成分的有效剂量。通常,将使用每一种的有效剂量。因而,例如,当本文提供的化合物与第二种药物或含有这样的其他药物的药物组合物组合使用时,所述微粒与第二种药物的重量比可以为约1,000:1至约1:1,000、或约200:1至约1:200。
本文提供的微粒和其他活性成分的组合通常也将在前述范围内,但是在每种情况下,应使用有效剂量的每种活性成分。
以下实施例中提供了本公开的实施方案的实例。以下实施例仅以示例的方式提出,并且有助于普通技术人员使用本公开。实施例不意图以任何方式另外限制本公开的范围。
实施例
实施例1
在健康受试者中评估利福平对缬苯那嗪甲苯磺酸盐的药代动力学的作用的I期、开放标签、单序列交叉研究
这是在总计12位健康受试者(6位男性和6位女性)中对缬苯那嗪甲苯磺酸盐的I期、开放标签、单序列交叉、药物相互作用研究。在提供知情同意书后,在第1天(研究药物施用的第一天)之前21天内,筛查受试者的参与本研究的合格性。符合合格性标准的受试者在第-1天(给药之前那天)的早晨入住研究中心。受试者在第1天和第11天在0800小时至1000小时接受单剂量80mg的缬苯那嗪甲苯磺酸盐。此外,受试者在第5天(在采集96小时PK样品后)至第14天在0830小时至1030小时每天一次接受600mg利福平(300mg×2个胶囊)。要求受试者在接受研究药物(缬苯那嗪甲苯磺酸盐和利福平)之前禁食过夜。在第15天(最终研究日或当提前终止时)在所有安全性评估和研究评估已经完成后,受试者离开研究中心。
在研究期间的计划时间内,采集血液样品用于PK分析NBI-98854及其代谢物、NBI-98782和NBI-136110以及用于利福平血浆浓度测定。在整个研究期间评估安全性。
口服施用NBI-98854 40mg胶囊。NBI-98854的剂量基于二甲苯磺酸盐(剂量表述为游离碱)。在研究期间在第1天和第11天,受试者接受单剂量NBI-98854 80mg(作为两个40mg胶囊)两次。
口服施用利福平300mg胶囊。在第5天(在采集96小时NBI-98854PK样品后)至第14天在0830小时至1030小时,受试者接受单剂量利福平600mg(作为两个300mg胶囊)。
药代动力学
在第1天和第11天NBI-98854给药之前30分钟和NBI-98854给药后15、30和45分钟以及1、1.5、2、3、4、8、12、18、24、48、72和96小时或当提前终止时,采集血液样品以测定NBI-98854及代谢物NBI-98782和NBI-136110的血浆浓度。
·评估NBI-98854、NBI-98782和NBI-136110的以下血浆PK参数:
·从0至24小时(AUC0-24)的血浆浓度对时间曲线下的面积(AUC)
·从0小时至最后可测量浓度(AUCtlast)的AUC
·从0小时外推至无限(AUC0-∞)的AUC
·最大血浆浓度(Cmax)
·在第一可测量浓度之前的时间(Tlag)
·表观终末半衰期(t1/2)
·至最大血浆浓度的时间(tmax)
·表观平均滞留时间(MRT)
·代谢物NBI-98782和NBI-136110与母体药物NBI-98854的摩尔比
仅计算NBI-98854的以下血浆PK参数:
·口服施用后表观全身性清除率(CL/F)
·口服施用后终末阶段期间的表观分布体积(Vz/F)
tmax、Tlag、t1/2、MRT和Vz/F的PK数据四舍五入为2位有效数字并且全部其他参数(AUC0-24、AUCtlast、AUC0-∞、Cmax和CL/F)四舍五入为3位有效数字。如果末位有效数字右侧的数字>5,则末位有效数字向上舍入,并且若其右侧的数字<4,则末位有效数字舍去。
在第5天和第11天给药前30分钟和利福平给药后1、2.5、3.5、7.5、11.5和23.5小时;在第6天至第10天和第12天至第13天利福平给药后2.5小时;在第14天利福平给药后2.5小时和8小时;以及在第15天(最终研究日或提前终止时)约0800小时,采集血液样品以测定利福平血浆浓度。计算利福平的以下血浆PK参数:AUC0-24、AUC0-tlast、Cmax和tmax。
tmax、Tlag、t1/2、MRT和Vz/F的PK数据四舍五入为2位有效数字并且全部其他参数(AUC0-24、AUC0-tlast、AUC0-∞、Cmax和CL/F)四舍五入为3位有效数字。如果末位有效数字右侧的数字≥5,则末位有效数字向上舍入,并且若其右侧的数字≤4,则末位有效数字舍去。
药代动力学结果
与仅施用NBI-98854相比,同时施用NBI-98854和利福平导致NBI-98854的Cmax下降约30%并且AUC0-∞下降约70%。几何平均值比率的90%置信区间(CI)(Cmax为57.9%至80.3%;并且AUC0-∞为25.5%至30.1%)位于80%至125%的“无影响”范围外,表明用利福平进行治疗影响NBI-98854的AUC0-∞和Cmax。当NBI-98854与利福平一起施用时,NBI-98854的平均t1/2从16小时降低至10小时。NBI-98854Cmax、AUC0-∞和t1/2的这种降低与利福平诱导型细胞色素P450(CYP)酶(例如,CYP3A4)在代谢NBI-98854中发挥明显作用的体外数据一致。
与仅施用NBI-98854相比,共同施用NBI-98854和利福平还导致活性代谢物NBI-98782的Cmax下降约50%并且AUC0-∞下降约80%。几何平均值比率的90%CI位于80%至125%的“无影响”范围外。当NBI-98854与利福平一起施用时,NBI-98782的平均t1/2从19小时降低至12小时。NBI-98782Cmax和AUC0-∞的这种降低可能是由于其形成因NBI-98854的生物利用度降低和/或利福平诱导型CYP酶(例如,CYP3A4)对NBI-98782的代谢增加而减少。
对于代谢物NBI-136110,平均Cmax增加1.4倍;然而,与仅施用NBI-98854相比,在用NBI-98854加利福平进行治疗后,平均AUC0-∞降低少约70%。几何平均值比率的90%CI位于80%至125%的“无影响”范围外。当NBI-98854与利福平一起施用时,NBI-136110的平均t1/2从27小时降低至12小时。NBI-136110Cmax的增加与体外数据一致,表明CYP3A4参与NBI-98854转化成NBI-136110。另外,NBI-136110的AUC和t1/2的降低提供了NBI-136110由利福平诱导型CYP酶(例如,CYP3A4)进一步代谢的证据。
药代动力学参数总结
下文提供用与利福平组合的NBI-98854或单一NBI-98854治疗后NBI-98854的AUC0-∞和Cmax的几何平均值比率和相关的90%CI。
a几何最小二乘平均值的比率基于使用对数变换(底数10)数据的的混合模式。
b几何平均值比率的90%置信区间基于使用对数变换(底数10)数据的最小二乘平均值
与单一NBI-98854相比,NBI-98854与利福平组合施用后NBI-98854的AUC0-∞和Cmax的几何平均值比率分别是27.7%和68.2%。AUC0-∞(25.5%至30.1%)和Cmax(57.9%至80.3%)的相应上限和下限90%CI界限位于80%至125%的“无影响”范围外,表明用利福平进行治疗对NBI-98854AUC0-∞和Cmax的作用。
下文总结用单一NBI-98854或NBI-98854与利福平组合治疗后NBI-98782的PK参数。
NBI-98854加利福平治疗后NBI-98782的平均Cmax比单一NBI-98854治疗后的平均Cmax低约50%。NBI-98854与利福平组合治疗后NBI-98782的平均AUC0-∞比单一NBI-98854治疗后的平均AUC0-∞低约80%。在NBI-98854加利福平治疗(3.0小时)和单一NBI-98854治疗(4.0小时)后,中位tmax值类似,并且在NBI-98854加利福平治疗后的平均t1/2比单一NBI-98854治疗(分别是12小时和19小时)后的平均t1/2低。
在单一NBI-98854治疗和NBI-98854与利福平组合治疗后,NBI-98782的AUC0-24、AUCtlast、t1/2和MRT的PK变异性(即,几何CV%)通常相似;但是在NBI-98854与利福平组合后,其Cmax的PK变异性较高。
与单一NBI-98854相比,NBI-98854与利福平组合施用后NBI-98782的AUC0-∞和Cmax的几何平均值比率分别是22.8%和48.5%。AUC0-∞(20.5%至25.4%)和Cmax(41.3%至56.9%)的相应上限和下限90%CI界限位于80%至125%的“无影响”范围外,表明用利福平进行治疗影响NBI-98782AUC0-∞和Cmax。
单一NBI-98854或NBI-98854与利福平组合的平均NBI-136110血浆浓度对时间的曲线示于以下。
NBI-98854与利福平组合治疗后的平均Cmax比单一NBI-98854治疗后的平均Cmax高约1.4倍。NBI-98854与利福平组合治疗后NBI-136110的平均AUC0-∞比单一NBI-98854治疗后的平均AUC0-∞低约70%。NBI-98854与利福平组合治疗后的中值tmax比单一NBI-98854治疗后的中值tmax短1.5小时(1.5小时与3.0小时)。NBI-98854与利福平组合治疗后NBI-136110的平均t1/2比单一NBI-98854治疗后的平均t1/2短约40%。在单一NBI-98854治疗和NBI-98854与利福平组合治疗后,NBI-136110的AUCtlast和t1/2的PK变异性(即,几何CV%)通常相似;但是在NBI-98854与利福平组合后,其AUC0-24、MRT和Cmax的PK变异性较低。
与单一NBI-98854相比,NBI-98854与利福平组合施用的后NBI-136110的AUC0-∞和Cmax的几何平均值比率分别是31.9%和139.5%。AUC0-∞(28.9%至35.2%)和Cmax(112.3%至173.3%)的90%CI位于80%至125%的“无影响”范围外,表明用利福平进行治疗对NBI-136110AUC0-∞和Cmax的作用。
与仅施用NBI-98854相比,同时施用NBI-98854和利福平导致NBI-98854的Cmax下降约30%并且AUC0-∞下降约70%。几何平均值比率的90%CI(Cmax为57.9%至80.3%;并且AUC0-∞为25.5%至30.1%)位于80%至125%的“无影响”范围外,表明用利福平进行治疗对NBI-98854AUC0-∞和Cmax的作用。当NBI-98854与利福平一起施用时,NBI-98854的平均t1/2从16小时降低至10小时。NBI-98854Cmax和AUC的这种降低与利福平诱导型CYP酶(例如,CYP3A4)在代谢NBI-98854中发挥显著作用的体外数据一致。
与仅施用NBI-98854相比,同时施用NBI-98854和利福平还导致活性代谢物NBI-98782的Cmax下降约50%并且AUC0-∞下降约80%。几何平均值比率的90%CI位于80%至125%的“无影响”范围外。当NBI-98854与利福平一起施用时,NBI-98782的平均t1/2从19小时降低至12小时。NBI-98782Cmax和AUC的这种降低可能是由于其形成因NBI-98854的生物利用度降低和/或利福平诱导型CYP酶(例如,CYP3A4)对NBI-98782的代谢增加而减少。
对于代谢物NBI-136110,平均Cmax增加1.4倍;然而,与仅施用NBI-98854相比,在用NBI-98854加利福平进行治疗后,平均AUC0-∞降低少约70%。几何平均值比率的90%CI位于80%至125%的“无影响”范围外。当NBI-98854与利福平一起施用时,NBI-136110的平均t1/2从27小时降低至12小时。NBI-136110的Cmax增加与体外数据一致,表明CYP3A4参与NBI-98854转化成NBI-136110。另外,NBI-136110的AUC0-∞降低提供了NBI-136110由利福平诱导型CYP酶(例如,CYP3A4)进一步代谢的证据。
安全性
基于不良事件(AE)、临床实验室试验、生命体征、体格检查和心电图(ECG)评估安全性。
统计方法:用描述性统计学并且在图中总结NBI-98854、其代谢物NBI-98782和NBI-136110以及利福平的血浆浓度。方差分析(ANOVA)模型用于比较与利福平一起施用的NBI-98854的AUC0-∞和Cmax(“试验”)与单一NBI-98854的AUC0-∞和Cmax(“参比”)。还评估了NBI-98854和利福平的代谢物的PK参数。使用描述性统计学总结安全性数据。
安全性结果
这项研究中未报告因AE所致的死亡、严重或重度治疗发生的不良事件(TEAE)或停止。在启用利福平后,全部12位受试者(100%)均出现色素尿。色素尿是利福平的已知的副作用。其他最频繁报告的AE是头痛(3位受试者,25.0%)。
除了色素尿以外,各治疗报告之间的AE的数目和类型不存在重大差异。在研究期间,临床实验室试验结果、生命体征量值或ECG参数在临床上没有显著变化,并且各自之间未记录到临床上重要的差异。大部分受试者在研究期间具有正常的体格检查并且认定没有异常发现在临床上是重要的。从基线至最终就诊,不存重大的体重变化。使用Fridericia式(QTcF)间期>450毫秒或离基线的最大增加>30毫秒,没有受试者具有校正的QT间期。
下文依据治疗总结经历TEAE的受试者的数目和百分数。
经历治疗发生的不良事件的受试者的数目和百分数(安全分析集)
a在第一剂量的(第1天)的NBI-98854时或之后、但在第一剂量的利福平之前发作。
b在第一剂量的利福平时或之后、但在第11天NBI-98854加利福平给药之前发作。
c在第11天NBI-98854加利福平给药时或之后发作。
注:受试者对于每个系统器官类型或优选术语可以具有多于一个TEAE。
结论
NBI-98854的主要代谢清除途径是形成活性代谢物NBI-98782的酯水解及形成NBI-136110的单氧化。体外研究已经提示,NBI-98854水解以形成NBI-98782可能以酶促方式(经由酯酶)和非酶促方式(经由化学水解)发生,而CYP3A4/5是涉及NBI-98854氧化代谢的主要酶。代谢物NBI-98782的氧化代谢主要由CYP2D6介导,以及来自CYP3A4/5(和可能其他酶)的贡献。鉴于CYP酶在代谢和消除NBI-98854中的作用,预期多效性CYP诱导剂如利福平将降低NBI-98854及其代谢物的全身暴露量。
来自本研究的数据提供了显示以下情况的临床数据:同时施用NBI-98854和利福平导致NBI-98854的全身暴露量下降,这与诱导型CYP酶(例如,CYP3A4)在代谢NBI-98854中发挥显著作用一致。NBI-98782的全身暴露量降低,这可能是由于(1)NBI-98854的生物利用度降低和/或(2)利福平诱导型CYP酶(例如,CYP3A4)对NBI-98782的代谢增加。利福平对NBI-136110暴露量测量值的作用以Cmax升高、但AUC下降为特征。NBI-136110的Cmax增加与体外数据一致,这表明CYP3A4参与NBI-98854转化成NBI-136110。预期这条途径的诱导将增加NBI-136110形成速率,如Cmax升高所证明。相反,NBI-136110的AUC0-∞和t1/2的降低提供了NBI-136110由肝脏CYP酶代谢并消除的证据。
总体上,NBI-98854在本研究中是良好耐受的。未报道死亡或严重或重度TEAE并且没有受试者因TEAE而停止研究。在研究期间,临床实验室试验结果、生命体征量值或ECG参数在临床上没有显著变化。
同时施用NBI-98854和利福平导致NBI-98854和NBI-98782的全身暴露量下降。
当单独施用或与利福平共同施用时,NBI-98854 80mg在健康的受试者中是良好耐受的。
实施例2:缬苯那嗪、四苯喹嗪及其代谢物的药理学表征
经口服施用,TBZ被还原以形成四种独立的异构仲醇代谢物,统称为二氢四苯喹嗪(DHTBZ),其含有三个非对称碳中心(C-2、C-3和C-11β),其可以假定产生八种立体异构体。然而,由于C-3和C-11β碳具有固定的相对构型,因此仅可能有四种立体异构体:(R,R,R-DHTBZ或(+)-α-DHTBZ(备用命名法(alternate nomenclature))或NBI-98782(实验室命名法);S,S,S-DHTBZ或(-)-α-DHTBZ或NBI-98771;S,R,R-DHTBZ或(+)-β-DHTBZ或NBI-98795;以及R,S,S-DHTBZ或(-)-β-DHTBZ或NBI-98772。
通过抑制[3H]-DHTBZ与大鼠前脑膜的结合,测量每种化合物的亲和力。还计算并展示了相对于R,R,R-DHTBZ的亲和力。数据报告为用于统计计算的Ki的负对数(pKi)和用于确定平均值和SEM的正态分布的结合参数。由平均pKi确定Ki值为10(-pKi)。R,R,R-DHTBZ立体异构体以最高亲和力与大鼠和人VMAT2两者结合(Ki=1.0至4.2nM)。相比之下,剩余三种DHTBZ立体异构体(S,R,R-DHTBZ、S,S,S-DHTBZ、R,S,S-DHTBZ)分别以9.7、250和690nM的Ki值与VMAT2结合。
大鼠前脑中的体外VMAT2结合亲和力
a使用同一研究中测定的Ki值,计算相对于R,R,R-DHTBZ的亲和力
缬苯那嗪(VBZ,NBI-98854)的主要代谢清除途径是水解(以形成R,R,R-DHTBZ)和单氧化(以形成代谢物NBI-136110)。R,R,R-DHTBZ和NBI-136110(VBZ的两种最丰富循环型代谢物)逐渐地形成并且它们的血浆浓度下降,并且半寿期与VBZ类似。
测试VBZ及其代谢物R,R,R-DHTBZ和NBI-136110抑制[3H]-DHTBZ与细胞系或天然组织中的VMAT2的结合的能力。通过抑制结合至人血小板或大鼠纹状体膜的[3H]-DHTBZ,测量每种化合物的亲和力。还计算并展示了相对于R,R,R-DHTBZ的亲和力。数据报告为用于统计计算的Ki的负对数(pKi)和正态分布的结合参数以用于确定平均值和SEM(每种组织中的每种化合物,n=4)。由平均pKi确定Ki值为10(-pKi)。初级代谢物R,R,R-DHTBZ是大鼠纹状体和人血小板匀浆中最强力的VMAT2抑制剂。
缬苯那嗪及其代谢物的体外VMAT2结合亲和力
VBZ和NBI-136110对VMAT2抑制具有相似的影响,但Ki值是R,R,R-DHTBZ的Ki值(更低的亲和力)的大概40-65倍。通过大鼠前脑中DHTBZ立体异构体(即,TBZ代谢物)的放射配体结合分析,证实了这些结果,所述结果还显示R,R,R-DHTBZ是最强力的VMAT2的抑制剂,随后是S,R,R-DHTBZ。相比而言,发现TBZ的另外两种初级代谢物S,S,S-DHTBZ和R,S,S-DHTBZ是不良的VMAT2抑制剂,其亲和力比R,R,R-DHTBZ弱大概60倍和160倍。
在多类别蛋白质靶标的广泛Cerep筛选中评估VBZ及其代谢物R,R,R-DHTBZ和NBI-136110对VMAT2以外的其他靶标的亲和力,所述的蛋白质靶标包括GPCR、细胞表面单胺转运体和离子通道(包括心脏钾通道)、人乙醚舞蹈样运动紊乱相关基因(human ether-à-go-go-related gene,HERG)。
对这些化合物的超过80种靶标的多靶标活性筛选(Cerep筛选)显示,VBZ及其代谢物R,R,R-DHTBZ和NBI-136110在1至10μM的浓度下以超过50%的形式不抑制同源配体与任何靶标的结合。相反,其他三种DHTBZ立体异构体(S,R,R-DHTBZ、S,S,S-DHTBZ、R,S,S-DHTBZ)(其为TBZ的代谢物而非VBZ的代谢物)对配体与多种受体亚型的结合显示出>50%的抑制,所述受体亚型包括血清素受体、多巴胺受体和肾上腺素能受体。结果表示为对照特异性结合的百分数:(受试化合物特异性结合/对照特异性结合)×100。全部化合物均在1或10μM终浓度下进行测试并且结果是作为Cerep(每种靶标下每种化合物n=2)下的初始筛选进行的较大的80种靶标组的节选。加粗的结果(>50%)表示靶标受体的活性。
缬苯那嗪和DHTBZ立体异构体对多巴胺受体、血清素受体和肾上腺素能受体的体外活性
a出于广谱筛选(broad panel screen)的目的,S,S,S-和R,S,S-代谢物作为50/50混合物进行测试。
为了更详细地描述单胺体系,对TBZ和VBZ的共同代谢物(R,R,R-DHTBZ)及TBZ和VBZ独有的其他相关代谢物的多巴胺受体亚型、血清素受体亚型和肾上腺素能受体亚型以及多巴胺转运体(DAT)、血清素转运体(SERT)和去甲肾上腺素转运体(NET)进行详细的放射配体结合试验。这种详细分析揭示R,R,R-DHTBZ对VMAT2转运体的高特异性和其他TBZ代谢物的非特异性活性,包括对多巴胺受体亚型和血清素受体亚型的相对高的亲和力。有趣的是,R,R,R-DHTBZ代谢物相对于单胺受体显示出最大的非选择性。TBZ代谢物或VBZ代谢物均对单胺转运体DAT、SERT或NET没有任何亲和力。为了完成VMAT2的选择性谱,在表达VMAT1的细胞中测试这些化合物对人VMAT1转运体的功能活性。尽管VMAT1的非选择性不可逆性高亲和力摄取抑制剂-利血平大幅度抑制通过VMAT1的摄取,但是在高达10μM的浓度下,不存在明显的TBZ、VBZ或其代谢物R,R,R-DHTBZ或NBI-136110的抑制活性。对于VMAT1和VMAT2两者,在未转染的宿主细胞中测量摄取并且发现其与在过量利血平存在下转染的细胞相似。
放射配体结合试验和广谱筛选表明,除了对VMAT2转运体的效力不同外,TBZ的两种其他DHTBZ代谢物(S,S,S-DHTBZ和R,S,S-DHTBZ)与D1受体和D2受体相互作用。由于VBZ不代谢成这些DHTBZ立体异构体中的任一种,故其直接或间接通过代谢物对突触后多巴胺受体的影响不存在。
另外,来自广谱筛选的结果显示,VBZ及其主要代谢物(R,R,R-DHTBZ和NBI-136110)对超过80个结合位点(包括受体、单胺转运体和离子通道)具有很小的亲和力或没有亲和力。该谱表明脱靶药理学效应的可能性低。此外,使用TBZ、VBZ及其代谢物R,R,R-DHTBZ和NBI-136110的摄取研究证实了这些化合物对VMAT2的选择性,因为与已知的VMAT1/VMAT2抑制剂利血平相比,它们对通过VMAT1的单胺的摄取没有明显影响。
使用药理作用的两种体内替代测量,明显地证明了VBZ的选择性和特异性。已知经由肾上腺素能活化和来自垂体的催乳素释放而发生的通过D2多巴胺受体得以调节的上睑下垂证明了用TBZ和VBZ的治疗之间的差异。TBZ、VBZ和R,R,R-DHTBZ以等同的方式诱导上睑下垂。这证实,通过给药TBZ或VBZ所形成的代谢物或者活性代谢物本身(R,R,R-DHTBZ)的给药均对影响突触前单胺释放的VMAT2具有活性(在这种情况下,与去甲肾上腺素释放有关)以特定地诱导上睑下垂。在相似治疗后,但这次使用催乳素释放作为多巴胺能调节的替代物,R,R,R-DHTBZ和VBZ(在更低的程度上)引起与TBZ相似的血清催乳素水平升高。
上文描述的多种实施方案可以组合以提供其他实施方案。本说明书中所引用的和/或申请数据表中所列的全部美国专利、美国专利申请公开、美国专利申请、外国专利、外国专利申请和非专利公开均通过引用整体并入本文。如有必要,可以修改实施方案的诸方面,以利用各专利、申请和公开的构思进一步提供其他实施方案。
可以根据以上详细描述对实施方案做出这些变化和其他改变。通常,在以下权利要求书中,所用术语不应当解释成将权利要求限制于说明书和权利要求书中公开的具体实施方案,而应当解释成包括全部可能的实施方案连同此权利要求书所享有的等同物的全部范围。因此,权利要求不受本公开限制。
Claims (78)
1.向有需要的患者施用选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂的方法,包括:
向所述患者施用治疗有效量的所述VMAT2抑制剂,以及
告知所述患者或医护工作者,不建议共同施用细胞色素P450 3A4(CYP3A4)强诱导剂。
2.根据权利要求1所述的方法,其中告知所述患者或医护工作者,应避免或停止共同施用CYP3A4强诱导剂。
3.向有需要的患者施用选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂的方法,其中所述患者正在用细胞色素P450 3A4(CYP3A4)强诱导剂进行治疗,包括:
停止所述CYP3A4强诱导剂的治疗,以及然后
向所述患者施用所述VMAT2抑制剂,从而避免所述VMAT2抑制剂与所述CYP3A4强诱导剂组合使用。
4.根据权利要求1至3中任一项所述的方法,其中所述CYP3A4强诱导剂选自奈韦拉平、戊巴比妥、苯妥英、鲁玛卡托(lumacaftor)、利福布汀、利福平、卡马西平、磷苯妥英、苯巴比妥、扑米酮、扑米酮、恩杂鲁胺、米托坦和贯叶连翘(St.John’s Wort)。
5.根据权利要求4所述的方法,其中所述CYP3A4强诱导剂选自利福平、卡马西平、苯妥英和贯叶连翘。
6.根据权利要求5所述的方法,其中所述CYP3A4强诱导剂是利福平。
7.根据权利要求1至6中任一项所述的方法,其中向所述患者施用所述VMAT2抑制剂以治疗神经或精神疾病或病症。
8.根据权利要求7所述的方法,其中神经或精神疾病或病症是多动性运动障碍、情感障碍、双相障碍、精神分裂症、情感分裂障碍、情感障碍中的躁狂、情感障碍中的抑郁、治疗难治性强迫性障碍、与Lesch-Nyhan综合征相关的神经功能障碍、与阿尔茨海默病相关的躁动、脆性X综合征或脆性X相关的震颤-共济失调综合征、自闭症谱系障碍、Rett综合征或舞蹈病-棘状红细胞增多症。
9.根据权利要求8所述的方法,其中所述神经或精神疾病或病症是多动性运动障碍。
10.根据权利要求9所述的方法,其中所述多动性运动障碍是迟发性运动障碍。
11.根据权利要求9所述的方法,其中所述多动性运动障碍是图雷特(Tourette)综合征。
12.根据权利要求9所述的方法,其中所述多动性运动障碍是亨廷顿病。
13.根据权利要求9所述的方法,其中所述多动性运动障碍是抽搐。
14.根据权利要求9所述的方法,其中所述多动性运动障碍是与亨廷顿病相关的舞蹈病。
15.根据权利要求9所述的方法,其中所述多动性运动障碍是共济失调、舞蹈病、肌张力障碍、亨廷顿病、肌阵挛、不宁腿综合征或震颤。
16.根据权利要求1至15中任一项所述的方法,其中所述VMAT2抑制剂经口服施用。
17.根据权利要求1至16中任一项所述的方法,其中所述VMAT2抑制剂以片剂或胶囊的形式施用。
18.根据权利要求1至17中任一项所述的方法,其中所述VMAT2抑制剂伴随或不伴随食物施用。
19.根据权利要求1至18中任一项所述的方法,其中所述VMAT2抑制剂是缬苯那嗪或其药物可接受的盐和/或同位素变体。
20.根据权利要求19所述的方法,其中所述VMAT2抑制剂是缬苯那嗪或其药物可接受的盐。
21.根据权利要求20所述的方法,其中所述VMAT2抑制剂是缬苯那嗪甲苯磺酸盐。
22.根据权利要求21所述的方法,其中所述VMAT2抑制剂是缬苯那嗪的二甲苯磺酸盐。
23.根据权利要求19所述的方法,其中所述VMAT2抑制剂是同位素变体,所述同位素变体是(2R,3R,11bR)-1,3,4,6,7,11b-六氢-9,10-二(甲氧基-d3)-3-(2-甲基丙基)-2H-苯并[a]喹嗪-2-基L-缬氨酸酯或其药物可接受的盐。
24.根据权利要求1至23中任一项所述的方法,其中所述VMAT2抑制剂以等同于约20mg至约160mg的缬苯那嗪游离碱的量施用。
25.根据权利要求24所述的方法,其中所述VMAT2抑制剂以等同于约20mg的缬苯那嗪游离碱的量施用。
26.根据权利要求24所述的方法,其中所述VMAT2抑制剂以等同于约40mg的缬苯那嗪游离碱的量施用。
27.根据权利要求24所述的方法,其中所述VMAT2抑制剂以等同于约60mg的缬苯那嗪游离碱的量施用。
28.根据权利要求24所述的方法,其中所述VMAT2抑制剂以等同于约80mg的缬苯那嗪游离碱的量施用。
29.根据权利要求24所述的方法,其中所述VMAT2抑制剂以等同于约120mg的缬苯那嗪游离碱的量施用。
30.根据权利要求1至23中任一项所述的方法,其中所述VMAT2抑制剂以第一量施用第一时间段并且随后所述量增加至第二量。
31.根据权利要求30所述的方法,其中所述第一时间段是一周。
32.根据权利要求30或31所述的方法,其中所述第一量等同于约40mg的缬苯那嗪游离碱。
33.根据权利要求30至32中任一项所述的方法,其中所述第二量等同于约80mg的缬苯那嗪游离碱。
34.根据权利要求1至23中任一项所述的方法,其中以足以在8小时的时间内实现每mL血浆约15ng至约60ng的(+)-α-DHTBZ的最大血浆浓度(Cmax)和每mL血浆至少15ng的(+)-α-DHTBZ的最小血浆浓度(Cmin)的量施用所述VMAT2抑制剂。
35.根据权利要求1至23中任一项所述的方法,其中以足以在12小时的时间内实现每mL血浆约15ng至约60ng的(+)-α-DHTBZ的最大血浆浓度(Cmax)和约为Cmax的约至少33%至50%的最小血浆浓度(Cmin)的量施用所述VMAT2抑制剂。
36.根据权利要求1至23中任一项所述的方法,其中所述VMAT2抑制剂以这样的量施用,所述量足以在约8小时至约24小时的时间段内实现:(i)每mL血浆约15ng至约60ng的(+)-α-DHTBZ的治疗浓度范围;以及(ii)每mL血浆至少15ng的(+)-α-DHTBZ的阈值浓度。
37.根据权利要求1至18中任一项所述的方法,其中所述VMAT2抑制剂是(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体。
38.根据权利要求37所述的方法,其中所述VMAT2抑制剂是(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐。
39.根据权利要求37所述的方法,其中所述VMAT2抑制剂是同位素变体,所述同位素变体是(+)-α-3-异丁基-9,10-二(甲氧基-d3)-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐。
40.用于治疗需要选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂的患者的组合物,包含治疗有效量的所述VMAT2抑制剂,
其中告知所述患者或医护工作者,不建议共同施用细胞色素P4503A4(CYP3A4)强诱导剂。
41.根据权利要求40所述的组合物,其中告知所述患者或医护工作者,应避免或停止共同施用所述CYP3A4强诱导剂。
42.用于治疗需要选自缬苯那嗪和(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体的囊泡单胺转运体2(VMAT2)抑制剂并且正在用细胞色素P450 3A4(CYP3A4)强诱导剂进行治疗的患者的组合物,包含
所述VMAT2抑制剂,
其中在将组合物施用于所述患者之前,停止所述CYP3A4强诱导剂的治疗,从而避免所述组合物与所述CYP3A4强诱导剂组合使用。
43.根据权利要求40至42中任一项所述的组合物,其中所述CYP3A4强诱导剂选自奈韦拉平、戊巴比妥、苯妥英、鲁玛卡托、利福布汀、利福平、卡马西平、磷苯妥英、苯巴比妥、扑米酮、扑米酮、恩杂鲁胺、米托坦和贯叶连翘。
44.根据权利要求43所述的组合物,其中所述CYP3A4强诱导剂选自利福平、卡马西平、苯妥英和贯叶连翘。
45.根据权利要求44所述的组合物,其中所述CYP3A4强诱导剂是利福平。
46.根据权利要求40至45中任一项所述的组合物,其中所述组合物用于治疗神经或精神疾病或病症。
47.根据权利要求46所述的组合物,其中神经系统疾病或障碍或精神疾病或障碍是多动性运动障碍、情感障碍、双相障碍、精神分裂症、情感分裂障碍、情感障碍中的躁狂、情感障碍中的抑郁、治疗难治性强迫性障碍、与Lesch-Nyhan综合征相关的神经功能障碍、与阿尔茨海默病相关的躁动、脆性X综合征或脆性X相关的震颤-共济失调综合征、自闭症谱系障碍、Rett综合征或舞蹈病-棘状红细胞增多症。
48.根据权利要求47所述的组合物,其中所述神经或精神疾病或病症是多动性运动障碍。
49.根据权利要求48所述的组合物,其中所述多动性运动障碍是迟发性运动障碍。
50.根据权利要求48所述的组合物,其中所述多动性运动障碍是图雷特综合征。
51.根据权利要求48所述的组合物,其中所述多动性运动障碍是亨廷顿病。
52.根据权利要求48所述的组合物,其中所述多动性运动障碍是抽搐。
53.根据权利要求48所述的组合物,其中所述多动性运动障碍是与亨廷顿病相关的舞蹈病。
54.根据权利要求48所述的组合物,其中所述多动性运动障碍是共济失调、舞蹈病、肌张力障碍、亨廷顿病、肌阵挛、不宁腿综合征或震颤。
55.根据权利要求40至54中任一项所述的组合物,特征在于,所述组合物经口服施用。
56.根据权利要求40至55中任一项所述的组合物,特征在于,所述组合物以片剂或胶囊的形式施用。
57.根据权利要求40至56中任一项所述的组合物,特征在于,所述组合物伴随或不伴随食物施用。
58.根据权利要求40至57中任一项所述的组合物,其中所述VMAT2抑制剂是缬苯那嗪或其药物可接受的盐和/或同位素变体。
59.根据权利要求58所述的组合物,其中所述VMAT2抑制剂是缬苯那嗪或其药物可接受的盐。
60.根据权利要求59所述的组合物,其中所述VMAT2抑制剂是缬苯那嗪甲苯磺酸盐。
61.根据权利要求60所述的组合物,其中所述VMAT2抑制剂是缬苯那嗪的二甲苯磺酸盐。
62.根据权利要求40至61中任一项所述的组合物,特征在于,所述组合物以等同于所述VMAT2抑制剂的约20mg至约120mg的缬苯那嗪游离碱的量施用。
63.根据权利要求62所述的组合物,特征在于,所述组合物以等同于所述VMAT2抑制剂的约20mg的缬苯那嗪游离碱的量施用。
64.根据权利要求62所述的组合物,特征在于,所述组合物以等同于所述VMAT2抑制剂的约40mg的缬苯那嗪游离碱的量施用。
65.根据权利要求62所述的组合物,特征在于,所述组合物以等同于所述VMAT2抑制剂的约80mg的缬苯那嗪游离碱的量施用。
66.根据权利要求62所述的组合物,特征在于,所述组合物以等同于所述VMAT2抑制剂的约60mg的缬苯那嗪游离碱的量施用。
67.根据权利要求62所述的组合物,特征在于,所述组合物以等同于所述VMAT2抑制剂的约120mg的缬苯那嗪游离碱的量施用。
68.根据权利要求40至61中任一项所述的组合物,特征在于,所述组合物以所述VMAT2抑制剂的第一量施用第一时间段并且随后所述量增加至第二量。
69.根据权利要求68所述的组合物,其中所述第一时间段是一周。
70.根据权利要求68或69所述的组合物,其中所述第一量等同于约40mg的缬苯那嗪游离碱。
71.根据权利要求68至70中任一项所述的组合物,其中所述第二量等同于约80mg的缬苯那嗪游离碱。
72.根据权利要求40至61中任一项所述的组合物,特征在于,以足以在8小时的时间内实现每mL血浆约15ng至约60ng的(+)-α-DHTBZ的最大血浆浓度(Cmax)和每mL血浆至少15ng的(+)-α-DHTBZ的最小血浆浓度(Cmin)的量施用所述组合物。
73.根据权利要求40至61中任一项所述的组合物,特征在于,以足以在12小时的时间内实现每mL血浆约15ng至约60ng的(+)-α-DHTBZ的最大血浆浓度(Cmax)和约为Cmax的约至少33%至50%的最小血浆浓度(Cmin)的量施用所述组合物。
74.根据权利要求40至61中任一项所述的组合物,特征在于,所述组合物以这样的量施用,所述量足以在约8小时至约24小时的时间段内实现:(i)每mL血浆约15ng至约60ng的(+)-α-DHTBZ的治疗浓度范围;以及(ii)每mL血浆至少15ng的(+)-α-DHTBZ的阈值浓度。
75.根据权利要求58所述的组合物,其中所述VMAT2抑制剂是同位素变体,所述同位素变体是(2R,3R,11bR)-1,3,4,6,7,11b-六氢-9,10-二(甲氧基-d3)-3-(2-甲基丙基)-2H-苯并[a]喹嗪-2-基L-缬氨酸酯或其药物可接受的盐。
76.根据权利要求40至57中任一项所述的组合物,其中所述VMAT2抑制剂是(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐和/或同位素变体。
77.根据权利要求76所述的组合物,其中所述VMAT2抑制剂是(+)-α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐。
78.根据权利要求76所述的组合物,其中所述VMAT2抑制剂是同位素变体,所述同位素变体是(+)-α-3-异丁基-9,10-二(甲氧基-d3)-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇或其药物可接受的盐。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762451605P | 2017-01-27 | 2017-01-27 | |
US62/451,605 | 2017-01-27 | ||
PCT/US2017/055877 WO2018140092A1 (en) | 2017-01-27 | 2017-10-10 | Methods for the administration of certain vmat2 inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110709071A true CN110709071A (zh) | 2020-01-17 |
Family
ID=62978647
Family Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201780097535.7A Pending CN111655034A (zh) | 2017-01-27 | 2017-10-10 | 施用某些vmat2抑制剂的方法 |
CN201780088736.0A Pending CN110709071A (zh) | 2017-01-27 | 2017-10-10 | 用于施用某些vmat2抑制剂的方法 |
CN202310682815.1A Pending CN116712434A (zh) | 2017-01-27 | 2017-10-10 | 施用某些vmat2抑制剂的方法 |
CN201780088897.XA Pending CN110769826A (zh) | 2017-01-27 | 2017-10-10 | 施用某些vmat2抑制剂的方法 |
CN201780088730.3A Pending CN110740731A (zh) | 2017-01-27 | 2017-10-10 | 施用某些vmat2抑制剂的方法 |
CN201780088766.1A Pending CN110740732A (zh) | 2017-01-27 | 2017-10-10 | 施用某些vmat2抑制剂的方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201780097535.7A Pending CN111655034A (zh) | 2017-01-27 | 2017-10-10 | 施用某些vmat2抑制剂的方法 |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310682815.1A Pending CN116712434A (zh) | 2017-01-27 | 2017-10-10 | 施用某些vmat2抑制剂的方法 |
CN201780088897.XA Pending CN110769826A (zh) | 2017-01-27 | 2017-10-10 | 施用某些vmat2抑制剂的方法 |
CN201780088730.3A Pending CN110740731A (zh) | 2017-01-27 | 2017-10-10 | 施用某些vmat2抑制剂的方法 |
CN201780088766.1A Pending CN110740732A (zh) | 2017-01-27 | 2017-10-10 | 施用某些vmat2抑制剂的方法 |
Country Status (12)
Country | Link |
---|---|
US (9) | US10874648B2 (zh) |
JP (11) | JP7107950B2 (zh) |
KR (10) | KR20190108149A (zh) |
CN (6) | CN111655034A (zh) |
AU (7) | AU2017395700B2 (zh) |
CA (5) | CA3051832A1 (zh) |
EA (5) | EA201991782A1 (zh) |
MX (6) | MX2019008868A (zh) |
MY (2) | MY191077A (zh) |
PH (5) | PH12019501734A1 (zh) |
SG (3) | SG11201906891RA (zh) |
WO (5) | WO2018140093A1 (zh) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20180075591A (ko) | 2015-10-30 | 2018-07-04 | 뉴로크린 바이오사이언시즈 인코퍼레이티드 | 발베나진 염 및 그의 다형체 |
HUE059065T2 (hu) | 2015-12-23 | 2022-10-28 | Neurocrine Biosciences Inc | Szintetikus eljárás (S)-(2R,3R,11BR)-3-izobutil-9,10-dimetoxi-2,3,4,6,7,11B-hexahidro-1H-pirido [2,1-A]izokinolin-2-il-2-amino-3-metilbutanoát-di(4-metilbenzolszulfonát) elõállítására |
CA3051832A1 (en) | 2017-01-27 | 2018-08-02 | Neurocrine Bioscienes, Inc. | Methods for the administration of certain vmat2 inhibitors |
GB201705306D0 (en) | 2017-04-01 | 2017-05-17 | Adeptio Pharmaceuticals Ltd | Pharmaceutical compositions |
GB201705304D0 (en) | 2017-04-01 | 2017-05-17 | Adeptio Pharmaceuticals Ltd | Pharmaceutical compositions |
GB201705302D0 (en) | 2017-04-01 | 2017-05-17 | Adeptio Pharmaceuticals Ltd | Pharmaceutical compositions |
GB201705303D0 (en) | 2017-04-01 | 2017-05-17 | Adeptio Pharmaceuticals Ltd | Pharmaceutical compositions |
TW201919622A (zh) | 2017-09-21 | 2019-06-01 | 美商紐羅克里生物科學有限公司 | 高劑量戊苯那嗪(valbenazine)調配物及組合物、方法以及相關套組 |
US10993941B2 (en) | 2017-10-10 | 2021-05-04 | Neurocrine Biosciences, Inc. | Methods for the administration of certain VMAT2 inhibitors |
EA202090932A1 (ru) | 2017-10-10 | 2021-05-20 | Нейрокрин Байосайенсиз, Инк | Способы введения некоторых vmat2-ингибиторов |
WO2019129100A1 (zh) | 2017-12-26 | 2019-07-04 | 苏州科睿思制药有限公司 | 一种Valbenazine二对甲苯磺酸盐的晶型及其制备方法和用途 |
JOP20200336A1 (ar) * | 2018-08-15 | 2020-12-22 | Neurocrine Biosciences Inc | طرق إعطاء مثبطات vmat2 معينة |
CN114340624A (zh) * | 2019-05-09 | 2022-04-12 | 纽罗克里生物科学有限公司 | 施用某些vmat2抑制剂的方法 |
US10940141B1 (en) | 2019-08-23 | 2021-03-09 | Neurocrine Biosciences, Inc. | Methods for the administration of certain VMAT2 inhibitors |
EP4362944A1 (en) | 2021-06-30 | 2024-05-08 | Neurocrine Biosciences, Inc. | Valbenazine for use in the add-on treatment of schizophrenia |
CA3221728A1 (en) | 2021-06-30 | 2023-01-05 | Grace S. LIANG | Valbenazine for use in the treatment of dyskinesia due to cerebral palsy |
WO2023023026A1 (en) * | 2021-08-16 | 2023-02-23 | Foresee Pharmaceuticals Co., Ltd. | Polymer depot compositions for sustained release delivery of vmat2 inhibitors |
CA3229341A1 (en) | 2021-08-20 | 2023-02-23 | Ryan TERRY-LORENZO | Methods of screening for vmat2 inhibitors |
WO2023039187A1 (en) * | 2021-09-10 | 2023-03-16 | ATAI Life Sciences AG | Ibogaine combination treatment |
WO2023076568A1 (en) * | 2021-10-29 | 2023-05-04 | Neurocrine Biosciences, Inc. | Valbenazine compositions |
WO2023172849A1 (en) | 2022-03-07 | 2023-09-14 | Neurocrine Biosciences, Inc. | Valbenazine, a vmat2 inhibitor, as a free base a tosylate or ditosylate salt, for use in the treatment of chorea associated with huntington's disease |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101553487A (zh) * | 2006-11-08 | 2009-10-07 | 纽罗克里生物科学有限公司 | 取代的3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇化合物和与其相关的方法 |
CN103003275A (zh) * | 2010-06-01 | 2013-03-27 | 奥斯拜客斯制药有限公司 | Vmat2的苯并喹啉酮抑制剂 |
CN104684555A (zh) * | 2012-09-18 | 2015-06-03 | 奥斯拜客斯制药有限公司 | 囊泡单胺转运体2的氘化苯并喹啉抑制剂的制剂药代动力学 |
US20160068526A1 (en) * | 2013-01-31 | 2016-03-10 | Auspex Pharmaceuticals, Inc. | Benzoquinolone inhibitors of vmat2 |
WO2016210180A2 (en) * | 2015-06-23 | 2016-12-29 | Neurocrine Biosciences, Inc. | Vmat2 inhibitors for treating neurological diseases or disorders |
Family Cites Families (113)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1068938A (en) | 1910-11-07 | 1913-07-29 | Gustav F Schulze | Vehicle-apron. |
US3536809A (en) | 1969-02-17 | 1970-10-27 | Alza Corp | Medication method |
US3598123A (en) | 1969-04-01 | 1971-08-10 | Alza Corp | Bandage for administering drugs |
US3845770A (en) | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US3916899A (en) | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
JPS5283918A (en) | 1976-01-01 | 1977-07-13 | Wellcome Found | Pharmaceutical composition |
US4008719A (en) | 1976-02-02 | 1977-02-22 | Alza Corporation | Osmotic system having laminar arrangement for programming delivery of active agent |
JPS5777697A (en) | 1980-11-04 | 1982-05-15 | Nippon Zoki Pharmaceut Co Ltd | Physiologically active substance nsq |
US4328245A (en) | 1981-02-13 | 1982-05-04 | Syntex (U.S.A.) Inc. | Carbonate diester solutions of PGE-type compounds |
US4410545A (en) | 1981-02-13 | 1983-10-18 | Syntex (U.S.A.) Inc. | Carbonate diester solutions of PGE-type compounds |
JPS57209225A (en) | 1981-06-18 | 1982-12-22 | Yamasa Shoyu Co Ltd | Antitumor activity intensifier |
US4409239A (en) | 1982-01-21 | 1983-10-11 | Syntex (U.S.A.) Inc. | Propylene glycol diester solutions of PGE-type compounds |
JPS6028987A (ja) | 1983-07-28 | 1985-02-14 | Chugai Pharmaceut Co Ltd | 新規ジゴキシン誘導体 |
HU196714B (en) | 1984-10-04 | 1989-01-30 | Monsanto Co | Process for producing non-aqueous composition comprising somatotropin |
IE58110B1 (en) | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
US5073543A (en) | 1988-07-21 | 1991-12-17 | G. D. Searle & Co. | Controlled release formulations of trophic factors in ganglioside-lipsome vehicle |
US5612059A (en) | 1988-08-30 | 1997-03-18 | Pfizer Inc. | Use of asymmetric membranes in delivery devices |
IT1229203B (it) | 1989-03-22 | 1991-07-25 | Bioresearch Spa | Impiego di acido 5 metiltetraidrofolico, di acido 5 formiltetraidrofolico e dei loro sali farmaceuticamente accettabili per la preparazione di composizioni farmaceutiche in forma a rilascio controllato attive nella terapia dei disturbi mentali organici e composizioni farmaceutiche relative. |
PH30995A (en) | 1989-07-07 | 1997-12-23 | Novartis Inc | Sustained release formulations of water soluble peptides. |
US5120548A (en) | 1989-11-07 | 1992-06-09 | Merck & Co., Inc. | Swelling modulated polymeric drug delivery device |
US5585112A (en) | 1989-12-22 | 1996-12-17 | Imarx Pharmaceutical Corp. | Method of preparing gas and gaseous precursor-filled microspheres |
IT1246382B (it) | 1990-04-17 | 1994-11-18 | Eurand Int | Metodo per la cessione mirata e controllata di farmaci nell'intestino e particolarmente nel colon |
US5733566A (en) | 1990-05-15 | 1998-03-31 | Alkermes Controlled Therapeutics Inc. Ii | Controlled release of antiparasitic agents in animals |
US5204329A (en) | 1990-06-11 | 1993-04-20 | Du Pont Merck Pharmaceutical Company | Treatment of organ transplantation rejection |
US5543390A (en) | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | Covalent microparticle-drug conjugates for biological targeting |
US5580578A (en) | 1992-01-27 | 1996-12-03 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
TW333456B (en) | 1992-12-07 | 1998-06-11 | Takeda Pharm Ind Co Ltd | A pharmaceutical composition of sustained-release preparation the invention relates to a pharmaceutical composition of sustained-release preparation which comprises a physiologically active peptide. |
US5591767A (en) | 1993-01-25 | 1997-01-07 | Pharmetrix Corporation | Liquid reservoir transdermal patch for the administration of ketorolac |
US6274552B1 (en) | 1993-03-18 | 2001-08-14 | Cytimmune Sciences, Inc. | Composition and method for delivery of biologically-active factors |
US5985307A (en) | 1993-04-14 | 1999-11-16 | Emory University | Device and method for non-occlusive localized drug delivery |
US5523092A (en) | 1993-04-14 | 1996-06-04 | Emory University | Device for local drug delivery and methods for using the same |
US6087324A (en) | 1993-06-24 | 2000-07-11 | Takeda Chemical Industries, Ltd. | Sustained-release preparation |
US6004534A (en) | 1993-07-23 | 1999-12-21 | Massachusetts Institute Of Technology | Targeted polymerized liposomes for improved drug delivery |
IT1270594B (it) | 1994-07-07 | 1997-05-07 | Recordati Chem Pharm | Composizione farmaceutica a rilascio controllato di moguisteina in sospensione liquida |
US5759542A (en) | 1994-08-05 | 1998-06-02 | New England Deaconess Hospital Corporation | Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases |
US5660854A (en) | 1994-11-28 | 1997-08-26 | Haynes; Duncan H | Drug releasing surgical implant or dressing material |
US6316652B1 (en) | 1995-06-06 | 2001-11-13 | Kosta Steliou | Drug mitochondrial targeting agents |
US5798119A (en) | 1995-06-13 | 1998-08-25 | S. C. Johnson & Son, Inc. | Osmotic-delivery devices having vapor-permeable coatings |
CA2224381A1 (en) | 1995-06-27 | 1997-01-16 | Takeda Chemical Industries, Ltd. | Method of producing sustained-release preparation |
TW448055B (en) | 1995-09-04 | 2001-08-01 | Takeda Chemical Industries Ltd | Method of production of sustained-release preparation |
JP2909418B2 (ja) | 1995-09-18 | 1999-06-23 | 株式会社資生堂 | 薬物の遅延放出型マイクロスフイア |
US6039975A (en) | 1995-10-17 | 2000-03-21 | Hoffman-La Roche Inc. | Colon targeted delivery system |
US5980945A (en) | 1996-01-16 | 1999-11-09 | Societe De Conseils De Recherches Et D'applications Scientifique S.A. | Sustained release drug formulations |
TW345603B (en) | 1996-05-29 | 1998-11-21 | Gmundner Fertigteile Gmbh | A noise control device for tracks |
US6264970B1 (en) | 1996-06-26 | 2001-07-24 | Takeda Chemical Industries, Ltd. | Sustained-release preparation |
US6419961B1 (en) | 1996-08-29 | 2002-07-16 | Takeda Chemical Industries, Ltd. | Sustained release microcapsules of a bioactive substance and a biodegradable polymer |
ZA977967B (en) | 1996-09-23 | 1999-03-04 | Lilly Co Eli | Combination therapy for treatment of psychoses |
NZ334914A (en) | 1996-10-01 | 2000-09-29 | Stanford Res Inst Int | Taste-masked microcapsule compositions and methods of manufacture using a phase seperation-coacervation technique |
CA2217134A1 (en) | 1996-10-09 | 1998-04-09 | Sumitomo Pharmaceuticals Co., Ltd. | Sustained release formulation |
ES2221019T3 (es) | 1996-10-31 | 2004-12-16 | Takeda Chemical Industries, Ltd. | Preparacion de liberacion mantenida. |
US6131570A (en) | 1998-06-30 | 2000-10-17 | Aradigm Corporation | Temperature controlling device for aerosol drug delivery |
WO1998027980A2 (en) | 1996-12-20 | 1998-07-02 | Takeda Chemical Industries, Ltd. | Method of producing a sustained-release preparation |
US5891474A (en) | 1997-01-29 | 1999-04-06 | Poli Industria Chimica, S.P.A. | Time-specific controlled release dosage formulations and method of preparing same |
US6120751A (en) | 1997-03-21 | 2000-09-19 | Imarx Pharmaceutical Corp. | Charged lipids and uses for the same |
US6060082A (en) | 1997-04-18 | 2000-05-09 | Massachusetts Institute Of Technology | Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery |
US6350458B1 (en) | 1998-02-10 | 2002-02-26 | Generex Pharmaceuticals Incorporated | Mixed micellar drug deliver system and method of preparation |
US6613358B2 (en) | 1998-03-18 | 2003-09-02 | Theodore W. Randolph | Sustained-release composition including amorphous polymer |
US6048736A (en) | 1998-04-29 | 2000-04-11 | Kosak; Kenneth M. | Cyclodextrin polymers for carrying and releasing drugs |
KR19990085365A (ko) | 1998-05-16 | 1999-12-06 | 허영섭 | 지속적으로 약물 조절방출이 가능한 생분해성 고분자 미립구 및그 제조방법 |
AU1321900A (en) | 1998-10-23 | 2000-05-15 | Sepracor, Inc. | Compositions and methods employing r(-) fluoxetine and other active ingredients |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US6271359B1 (en) | 1999-04-14 | 2001-08-07 | Musc Foundation For Research Development | Tissue-specific and pathogen-specific toxic agents and ribozymes |
EP1313473A2 (en) | 2000-08-30 | 2003-05-28 | Pfizer Products Inc. | Sustained release formulations for growth hormone secretagogues |
CA2487732C (en) | 2002-05-28 | 2013-10-15 | Bette Pollard | Cardiac glycosides to treat cystic fibrosis and other il-8 dependent disorders |
WO2004026258A2 (en) | 2002-09-19 | 2004-04-01 | University Of Utah Research Foundation | Modulating vesicular monoamine transporter trafficking and function: a novel approach for the treatment of parkinson’s disease |
US7230097B2 (en) | 2003-03-10 | 2007-06-12 | Lupin Ltd. | Process for preparation of 7-[α-Amino (4-hydroxyphenyl) acetamido]-3-substituted-3-cephem-4-carboxylic acid |
GB0307259D0 (en) | 2003-03-28 | 2003-05-07 | Glaxo Group Ltd | Process |
GB2410947B (en) | 2004-02-11 | 2008-09-17 | Cambridge Lab Ltd | Pharmaceutical compounds |
AR049200A1 (es) | 2004-06-04 | 2006-07-05 | Genentech Inc | Metodo para tratar esclerosis multiple con una composicion que contiene un anticuerpo cd20 |
CA2582022C (en) | 2004-09-30 | 2021-05-18 | Vanda Pharmaceuticals, Inc. | Methods for the administration of iloperidone |
EP1804807B1 (en) | 2004-10-28 | 2008-12-03 | Wyeth a Corporation of the State of Delaware | Coadministration of tigecycline and digoxin |
WO2006053067A2 (en) | 2004-11-09 | 2006-05-18 | Prestwick Pharmaceuticals, Inc. | Combination of amantadine and a tetrabenazine compound for treating hyperkinetic disorders |
ATE415968T1 (de) | 2005-08-06 | 2008-12-15 | Cambridge Lab Ireland Ltd | 3,11b-cis-dihydrotetrabanezin zur behandlung von schizophrenie und anderen psychosen |
US20100076087A1 (en) | 2005-10-06 | 2010-03-25 | Auspex Pharmaceuticals, Inc. | Methods of reduction of interpatient variability |
GB0721669D0 (en) | 2007-11-02 | 2007-12-12 | Cambridge Lab Ireland Ltd | Pharmaceutical compounds |
US8158620B2 (en) | 2008-01-18 | 2012-04-17 | Eisai R&D Management Co., Ltd. | Fused aminodihydrothiazine derivatives |
GB2462611A (en) | 2008-08-12 | 2010-02-17 | Cambridge Lab | Pharmaceutical composition comprising tetrabenazine |
US20110053866A1 (en) | 2008-08-12 | 2011-03-03 | Biovail Laboratories International (Barbados) S.R.L. | Pharmaceutical compositions |
GB2463451A (en) | 2008-09-08 | 2010-03-17 | Cambridge Lab | 3, 11b cis-dihydrotetrabenazine compounds for use in the treatment of dementia |
GB2463452A (en) | 2008-09-08 | 2010-03-17 | Cambridge Lab | Desmethyl derivatives of tetrabenazine and pharmaceutical compositions thereof |
NZ591615A (en) | 2008-09-18 | 2012-07-27 | Auspex Pharmaceuticals Inc | Benzoquinoline inhibitors of vesicular monoamine transporter 2 |
US20100096319A1 (en) | 2008-10-17 | 2010-04-22 | General Electric Company | Separator assembly |
SI2417267T1 (sl) | 2009-04-06 | 2017-02-28 | Vanda Pharmaceuticals Inc. | Postopek zdravljenja na podlagi polimorfizmov gena KCNQ1 |
EP2464340A2 (en) | 2009-08-12 | 2012-06-20 | Valeant International (Barbados) SRL | Pharmaceutical compositions with tetrabenazine |
WO2012153341A1 (en) | 2011-05-12 | 2012-11-15 | Arch Pharmalabs Limited | A process for the preparation of iloperidone and pharmaceutically acceptable salts thereof |
CA2893542C (en) * | 2012-12-18 | 2022-07-19 | Vanda Pharmaceuticals Inc. | Use of tasimelteon in the treatment of circadian rhythm disorders |
WO2015077521A1 (en) * | 2013-11-22 | 2015-05-28 | Auspex Pharmaceuticals, Inc. | Benzoquinoline inhibitors of vesicular monoamine transporter 2 |
EA201691512A1 (ru) | 2014-01-27 | 2017-01-30 | Оспекс Фармасьютикалз, Инк. | Бензохинолиновые ингибиторы везикулярного переносчика моноамина 2 |
CN113413385A (zh) | 2014-02-07 | 2021-09-21 | 纽罗克里生物科学有限公司 | 包含抗精神病药物和vmat2抑制剂的药物组合物及其用途 |
EA201691582A1 (ru) | 2014-02-07 | 2017-01-30 | Оспекс Фармасьютикалз, Инк. | Новые фармацевтические препараты |
IL248745B (en) | 2014-05-06 | 2022-07-01 | Neurocrine Biosciences | (s)-2-amino-3-methyl butyric acid (r2, r3, rb11)-3 azazobutyl-9,10-dimethoxy-1,3,4,6,711b-hexahydro-h2-pyrido[a-1,2 ] isoquinoline-2-yl ester for use in the treatment of Tardib Discenza |
ES2960717T3 (es) | 2015-02-06 | 2024-03-06 | Neurocrine Biosciences Inc | [9,10-Dimetoxi-3-(2-metilpropil)-1H,2H,3H,4H,6H,7H,11BH-pirido-[2,1-A]isoquinolin-2-il]metanol y compuestos, composiciones y métodos relacionados con el mismo |
PL3265085T3 (pl) | 2015-03-06 | 2022-11-07 | Auspex Pharmaceuticals, Inc. | Sposoby leczenia zaburzeń związanych z nieprawidłowymi ruchami mimowolnymi |
KR20180075591A (ko) | 2015-10-30 | 2018-07-04 | 뉴로크린 바이오사이언시즈 인코퍼레이티드 | 발베나진 염 및 그의 다형체 |
HUE059065T2 (hu) | 2015-12-23 | 2022-10-28 | Neurocrine Biosciences Inc | Szintetikus eljárás (S)-(2R,3R,11BR)-3-izobutil-9,10-dimetoxi-2,3,4,6,7,11B-hexahidro-1H-pirido [2,1-A]izokinolin-2-il-2-amino-3-metilbutanoát-di(4-metilbenzolszulfonát) elõállítására |
JP2020500875A (ja) | 2016-12-02 | 2020-01-16 | ニューロクライン バイオサイエンシーズ,インコーポレイテッド | 統合失調症または統合失調感情障害を処置するためのバルベナジンの使用 |
CA3051832A1 (en) | 2017-01-27 | 2018-08-02 | Neurocrine Bioscienes, Inc. | Methods for the administration of certain vmat2 inhibitors |
WO2018164996A1 (en) | 2017-03-06 | 2018-09-13 | Neurocrine Biosciences, Inc. | Dosing regimen for valbenazine |
AU2018241940B2 (en) | 2017-04-01 | 2023-09-28 | Adeptio Pharmaceuticals Limited | Dihydrotetrabenazine for use in the treatment a movement disorder |
CA3057543A1 (en) | 2017-04-01 | 2018-10-04 | Adeptio Pharmaceuticals Limited | (+)-alpha-dihydrotetrabenazine for use in the treatment a movement disorder |
JOP20190239A1 (ar) | 2017-04-19 | 2019-10-09 | Neurocrine Biosciences Inc | مركبات مثبطة لـ vmat2 وتركيبات منها |
US20200179352A1 (en) | 2017-04-26 | 2020-06-11 | Neurocrine Biosciences, Inc. | Use of valbenazine for treating levodopa-induced dyskinesia |
JP2020520380A (ja) * | 2017-05-16 | 2020-07-09 | ボウ リバー エルエルシー | 処置法 |
US10857144B2 (en) * | 2017-05-16 | 2020-12-08 | Bow River LLC | Methods of treatment |
TW201919622A (zh) | 2017-09-21 | 2019-06-01 | 美商紐羅克里生物科學有限公司 | 高劑量戊苯那嗪(valbenazine)調配物及組合物、方法以及相關套組 |
US10993941B2 (en) | 2017-10-10 | 2021-05-04 | Neurocrine Biosciences, Inc. | Methods for the administration of certain VMAT2 inhibitors |
EA202090932A1 (ru) | 2017-10-10 | 2021-05-20 | Нейрокрин Байосайенсиз, Инк | Способы введения некоторых vmat2-ингибиторов |
WO2019104141A1 (en) | 2017-11-22 | 2019-05-31 | Teva Pharmaceuticals Usa, Inc. | Solid state form of valbenazine |
SG11202011544UA (en) | 2018-06-14 | 2020-12-30 | Neurocrine Biosciences Inc | Vmat2 inhibitor compounds, compositions, and methods relating thereto |
JOP20200336A1 (ar) | 2018-08-15 | 2020-12-22 | Neurocrine Biosciences Inc | طرق إعطاء مثبطات vmat2 معينة |
CN114340624A (zh) | 2019-05-09 | 2022-04-12 | 纽罗克里生物科学有限公司 | 施用某些vmat2抑制剂的方法 |
US10689380B1 (en) | 2019-07-30 | 2020-06-23 | Farmhispania S.A. | Crystalline forms of valbenazine ditosylate |
US10940141B1 (en) | 2019-08-23 | 2021-03-09 | Neurocrine Biosciences, Inc. | Methods for the administration of certain VMAT2 inhibitors |
-
2017
- 2017-10-10 CA CA3051832A patent/CA3051832A1/en active Granted
- 2017-10-10 KR KR1020197024657A patent/KR20190108149A/ko active Application Filing
- 2017-10-10 KR KR1020237007871A patent/KR20230038601A/ko not_active Application Discontinuation
- 2017-10-10 WO PCT/US2017/055907 patent/WO2018140093A1/en active Application Filing
- 2017-10-10 CA CA3051830A patent/CA3051830A1/en active Pending
- 2017-10-10 KR KR1020197024655A patent/KR20190108147A/ko active Application Filing
- 2017-10-10 WO PCT/US2017/055980 patent/WO2018140096A1/en active Application Filing
- 2017-10-10 KR KR1020237041673A patent/KR20230169457A/ko not_active Application Discontinuation
- 2017-10-10 MY MYPI2019004293A patent/MY191077A/en unknown
- 2017-10-10 CN CN201780097535.7A patent/CN111655034A/zh active Pending
- 2017-10-10 JP JP2019540650A patent/JP7107950B2/ja active Active
- 2017-10-10 CA CA3051834A patent/CA3051834A1/en active Granted
- 2017-10-10 US US16/481,033 patent/US10874648B2/en active Active
- 2017-10-10 MX MX2019008868A patent/MX2019008868A/es unknown
- 2017-10-10 CN CN201780088736.0A patent/CN110709071A/zh active Pending
- 2017-10-10 JP JP2020520311A patent/JP7090151B2/ja active Active
- 2017-10-10 JP JP2019540570A patent/JP7199361B2/ja active Active
- 2017-10-10 KR KR1020207012774A patent/KR20200066662A/ko not_active Application Discontinuation
- 2017-10-10 MX MX2020003462A patent/MX2020003462A/es unknown
- 2017-10-10 US US16/481,037 patent/US20200093808A1/en not_active Abandoned
- 2017-10-10 MY MYPI2019004292A patent/MY195934A/en unknown
- 2017-10-10 AU AU2017395700A patent/AU2017395700B2/en active Active
- 2017-10-10 AU AU2017395701A patent/AU2017395701B2/en active Active
- 2017-10-10 EA EA201991782A patent/EA201991782A1/ru unknown
- 2017-10-10 CA CA3051829A patent/CA3051829A1/en active Pending
- 2017-10-10 EA EA201991780A patent/EA201991780A1/ru unknown
- 2017-10-10 KR KR1020237041797A patent/KR20230170135A/ko not_active Application Discontinuation
- 2017-10-10 AU AU2017395702A patent/AU2017395702B2/en active Active
- 2017-10-10 AU AU2017395703A patent/AU2017395703B2/en active Active
- 2017-10-10 JP JP2019540568A patent/JP7199360B2/ja active Active
- 2017-10-10 WO PCT/US2017/055931 patent/WO2018140094A1/en active Application Filing
- 2017-10-10 SG SG11201906891RA patent/SG11201906891RA/en unknown
- 2017-10-10 US US16/481,029 patent/US20190381016A1/en not_active Abandoned
- 2017-10-10 CN CN202310682815.1A patent/CN116712434A/zh active Pending
- 2017-10-10 JP JP2019540557A patent/JP7199359B2/ja active Active
- 2017-10-10 EA EA202090676A patent/EA202090676A1/ru unknown
- 2017-10-10 KR KR1020197024656A patent/KR20190108148A/ko not_active IP Right Cessation
- 2017-10-10 KR KR1020207030652A patent/KR20200126430A/ko active Application Filing
- 2017-10-10 WO PCT/US2017/055965 patent/WO2018140095A2/en active Application Filing
- 2017-10-10 SG SG11201906883SA patent/SG11201906883SA/en unknown
- 2017-10-10 KR KR1020237041798A patent/KR20230170136A/ko not_active Application Discontinuation
- 2017-10-10 AU AU2017395704A patent/AU2017395704B8/en active Active
- 2017-10-10 MX MX2019008855A patent/MX2019008855A/es unknown
- 2017-10-10 EA EA201991784A patent/EA201991784A1/ru unknown
- 2017-10-10 SG SG11201906885TA patent/SG11201906885TA/en unknown
- 2017-10-10 CN CN201780088897.XA patent/CN110769826A/zh active Pending
- 2017-10-10 KR KR1020197024654A patent/KR20190108146A/ko not_active Application Discontinuation
- 2017-10-10 MX MX2019008853A patent/MX2019008853A/es unknown
- 2017-10-10 CN CN201780088730.3A patent/CN110740731A/zh active Pending
- 2017-10-10 CA CA3078719A patent/CA3078719A1/en active Pending
- 2017-10-10 CN CN201780088766.1A patent/CN110740732A/zh active Pending
- 2017-10-10 WO PCT/US2017/055877 patent/WO2018140092A1/en active Application Filing
- 2017-10-10 MX MX2019008854A patent/MX2019008854A/es unknown
- 2017-10-10 EA EA201991786A patent/EA201991786A1/ru unknown
-
2019
- 2019-07-25 MX MX2022007141A patent/MX2022007141A/es unknown
- 2019-07-26 PH PH12019501734A patent/PH12019501734A1/en unknown
- 2019-07-26 PH PH12019501732A patent/PH12019501732A1/en unknown
- 2019-07-26 PH PH12019501740A patent/PH12019501740A1/en unknown
- 2019-07-26 PH PH12019501744A patent/PH12019501744A1/en unknown
-
2020
- 2020-04-08 PH PH12020550238A patent/PH12020550238A1/en unknown
- 2020-05-08 US US16/870,423 patent/US10952997B2/en active Active
- 2020-05-08 US US16/870,706 patent/US10857137B2/en active Active
- 2020-05-08 US US16/870,572 patent/US11040029B2/en active Active
- 2020-10-17 US US17/073,304 patent/US10912771B1/en active Active
- 2020-10-26 US US17/080,343 patent/US11439629B2/en active Active
- 2020-12-17 US US17/125,190 patent/US20210169862A1/en not_active Abandoned
-
2022
- 2022-01-24 JP JP2022008580A patent/JP2022040408A/ja not_active Withdrawn
- 2022-05-12 AU AU2022203201A patent/AU2022203201B2/en active Active
- 2022-05-17 AU AU2022203327A patent/AU2022203327A1/en active Pending
- 2022-07-14 JP JP2022113075A patent/JP2022137219A/ja active Pending
- 2022-10-04 JP JP2022160177A patent/JP2022174343A/ja active Pending
- 2022-10-05 JP JP2022160831A patent/JP2022174344A/ja active Pending
- 2022-10-05 JP JP2022160833A patent/JP2022174345A/ja active Pending
-
2023
- 2023-09-15 JP JP2023149999A patent/JP2023161033A/ja active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101553487A (zh) * | 2006-11-08 | 2009-10-07 | 纽罗克里生物科学有限公司 | 取代的3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇化合物和与其相关的方法 |
CN103003275A (zh) * | 2010-06-01 | 2013-03-27 | 奥斯拜客斯制药有限公司 | Vmat2的苯并喹啉酮抑制剂 |
CN104684555A (zh) * | 2012-09-18 | 2015-06-03 | 奥斯拜客斯制药有限公司 | 囊泡单胺转运体2的氘化苯并喹啉抑制剂的制剂药代动力学 |
US20160068526A1 (en) * | 2013-01-31 | 2016-03-10 | Auspex Pharmaceuticals, Inc. | Benzoquinolone inhibitors of vmat2 |
WO2016210180A2 (en) * | 2015-06-23 | 2016-12-29 | Neurocrine Biosciences, Inc. | Vmat2 inhibitors for treating neurological diseases or disorders |
Non-Patent Citations (4)
Title |
---|
ESTHER S. KIM: "Valbenazine: First Global Approval", 《DURGS》 * |
FUMIYOSHI YAMASHITA等: "Modeling of Rifampicin-Induced CYP3A4 Activation Dynamics for the Prediction of Clinical Drug-Drug Interactions from In Vitro Data", 《PLOS ONE》 * |
LESLIE CITROME: "Valbenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication-What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?", 《INT J CLIN PRACT.》 * |
THOMAS MULLER: "Valbenazine granted breakthrough drug status for treating tardive dyskinesia", 《EXPERT OPIN. INVESTIG. DRUGS》 * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110709071A (zh) | 用于施用某些vmat2抑制剂的方法 | |
CN111836543A (zh) | 施用某些vmat2抑制剂的方法 |
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 | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40016560 Country of ref document: HK |