WO2021101875A1 - Compositions and methods for treating disorders ameliorated by muscarinic receptor activation - Google Patents
Compositions and methods for treating disorders ameliorated by muscarinic receptor activation Download PDFInfo
- Publication number
- WO2021101875A1 WO2021101875A1 PCT/US2020/060859 US2020060859W WO2021101875A1 WO 2021101875 A1 WO2021101875 A1 WO 2021101875A1 US 2020060859 W US2020060859 W US 2020060859W WO 2021101875 A1 WO2021101875 A1 WO 2021101875A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- xanomeline
- trospium
- salt
- beads
- administered
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 233
- 239000000203 mixture Substances 0.000 title description 66
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 title description 23
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 title description 23
- 230000004913 activation Effects 0.000 title description 6
- 230000001668 ameliorated effect Effects 0.000 title description 5
- 229950006755 xanomeline Drugs 0.000 claims abstract description 448
- JOLJIIDDOBNFHW-UHFFFAOYSA-N xanomeline Chemical compound CCCCCCOC1=NSN=C1C1=CCCN(C)C1 JOLJIIDDOBNFHW-UHFFFAOYSA-N 0.000 claims abstract description 413
- OYYDSUSKLWTMMQ-JKHIJQBDSA-N trospium Chemical compound [N+]12([C@@H]3CC[C@H]2C[C@H](C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 OYYDSUSKLWTMMQ-JKHIJQBDSA-N 0.000 claims abstract description 276
- 229960001491 trospium Drugs 0.000 claims abstract description 268
- 239000011324 bead Substances 0.000 claims abstract description 224
- 150000003839 salts Chemical class 0.000 claims abstract description 179
- 239000008203 oral pharmaceutical composition Substances 0.000 claims abstract description 48
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 44
- 238000004448 titration Methods 0.000 claims abstract description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 26
- 201000010099 disease Diseases 0.000 claims abstract description 19
- RVCSYOQWLPPAOA-CVPHZBIISA-M [(5s)-spiro[8-azoniabicyclo[3.2.1]octane-8,1'-azolidin-1-ium]-3-yl] 2-hydroxy-2,2-diphenylacetate;chloride Chemical compound [Cl-].[N+]12([C@H]3CCC2CC(C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 RVCSYOQWLPPAOA-CVPHZBIISA-M 0.000 claims description 151
- 229960001530 trospium chloride Drugs 0.000 claims description 151
- 238000011282 treatment Methods 0.000 claims description 109
- 229940068196 placebo Drugs 0.000 claims description 71
- 239000000902 placebo Substances 0.000 claims description 71
- 239000002775 capsule Substances 0.000 claims description 58
- SJSVWTMVMBGIHQ-LREBCSMRSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;3-hexoxy-4-(1-methyl-3,6-dihydro-2h-pyridin-5-yl)-1,2,5-thiadiazole Chemical group OC(=O)[C@H](O)[C@@H](O)C(O)=O.CCCCCCOC1=NSN=C1C1=CCCN(C)C1 SJSVWTMVMBGIHQ-LREBCSMRSA-N 0.000 claims description 38
- 239000000454 talc Substances 0.000 claims description 38
- 229910052623 talc Inorganic materials 0.000 claims description 38
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 35
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 35
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 35
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 35
- 230000001965 increasing effect Effects 0.000 claims description 34
- 239000002552 dosage form Substances 0.000 claims description 29
- 239000012458 free base Substances 0.000 claims description 25
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 24
- 230000009467 reduction Effects 0.000 claims description 19
- 206010047700 Vomiting Diseases 0.000 claims description 18
- 230000008859 change Effects 0.000 claims description 17
- 238000004090 dissolution Methods 0.000 claims description 17
- 230000036772 blood pressure Effects 0.000 claims description 16
- 230000008673 vomiting Effects 0.000 claims description 14
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 13
- 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 claims description 13
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 13
- 229940095259 butylated hydroxytoluene Drugs 0.000 claims description 13
- 230000007423 decrease Effects 0.000 claims description 13
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 12
- 206010028813 Nausea Diseases 0.000 claims description 12
- 235000010323 ascorbic acid Nutrition 0.000 claims description 12
- 229960005070 ascorbic acid Drugs 0.000 claims description 12
- 239000011668 ascorbic acid Substances 0.000 claims description 12
- 206010013781 dry mouth Diseases 0.000 claims description 12
- 229960001021 lactose monohydrate Drugs 0.000 claims description 12
- 230000008693 nausea Effects 0.000 claims description 12
- 206010001022 Acute psychosis Diseases 0.000 claims description 11
- 230000002829 reductive effect Effects 0.000 claims description 11
- 230000001939 inductive effect Effects 0.000 claims description 10
- 238000007449 liver function test Methods 0.000 claims description 10
- 238000003745 diagnosis Methods 0.000 claims description 9
- 208000011580 syndromic disease Diseases 0.000 claims description 9
- 230000035487 diastolic blood pressure Effects 0.000 claims description 8
- 206010042772 syncope Diseases 0.000 claims description 8
- 230000035488 systolic blood pressure Effects 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 208000034332 Body integrity dysphoria Diseases 0.000 description 154
- 235000002639 sodium chloride Nutrition 0.000 description 129
- 239000003814 drug Substances 0.000 description 75
- 238000000576 coating method Methods 0.000 description 61
- -1 for example Chemical class 0.000 description 59
- 239000011248 coating agent Substances 0.000 description 53
- 229940079593 drug Drugs 0.000 description 46
- 239000002245 particle Substances 0.000 description 36
- 230000002411 adverse Effects 0.000 description 35
- 230000000694 effects Effects 0.000 description 30
- 238000009472 formulation Methods 0.000 description 29
- 238000009826 distribution Methods 0.000 description 28
- 230000002354 daily effect Effects 0.000 description 23
- 208000028017 Psychotic disease Diseases 0.000 description 21
- 230000008569 process Effects 0.000 description 20
- 230000001713 cholinergic effect Effects 0.000 description 19
- 239000000463 material Substances 0.000 description 19
- 239000008194 pharmaceutical composition Substances 0.000 description 19
- 238000005563 spheronization Methods 0.000 description 18
- 239000000546 pharmaceutical excipient Substances 0.000 description 17
- 238000009825 accumulation Methods 0.000 description 16
- 208000024891 symptom Diseases 0.000 description 16
- 239000002702 enteric coating Substances 0.000 description 15
- 238000009505 enteric coating Methods 0.000 description 15
- 229920000642 polymer Polymers 0.000 description 15
- 238000002560 therapeutic procedure Methods 0.000 description 14
- 238000013265 extended release Methods 0.000 description 13
- 238000001125 extrusion Methods 0.000 description 13
- 239000012535 impurity Substances 0.000 description 13
- 239000000945 filler Substances 0.000 description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 12
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000011230 binding agent Substances 0.000 description 11
- 230000002746 orthostatic effect Effects 0.000 description 11
- 208000008454 Hyperhidrosis Diseases 0.000 description 10
- 239000005557 antagonist Substances 0.000 description 10
- 230000003247 decreasing effect Effects 0.000 description 10
- 230000003551 muscarinic effect Effects 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 239000004094 surface-active agent Substances 0.000 description 10
- 229920001577 copolymer Polymers 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 239000012530 fluid Substances 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000003963 antioxidant agent Substances 0.000 description 8
- 235000006708 antioxidants Nutrition 0.000 description 8
- 230000006872 improvement Effects 0.000 description 8
- 238000003860 storage Methods 0.000 description 8
- 206010012735 Diarrhoea Diseases 0.000 description 7
- 206010039424 Salivary hypersecretion Diseases 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 239000000164 antipsychotic agent Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 239000001913 cellulose Substances 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 238000013270 controlled release Methods 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 7
- 238000012216 screening Methods 0.000 description 7
- 210000000813 small intestine Anatomy 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- 230000035900 sweating Effects 0.000 description 7
- 206010012239 Delusion Diseases 0.000 description 6
- 208000004547 Hallucinations Diseases 0.000 description 6
- 230000003213 activating effect Effects 0.000 description 6
- 230000001078 anti-cholinergic effect Effects 0.000 description 6
- 235000010980 cellulose Nutrition 0.000 description 6
- 229920002678 cellulose Polymers 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 231100000868 delusion Toxicity 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 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 6
- 229960003943 hypromellose Drugs 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229920000609 methyl cellulose Polymers 0.000 description 6
- 235000010981 methylcellulose Nutrition 0.000 description 6
- 239000001923 methylcellulose Substances 0.000 description 6
- 239000004014 plasticizer Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 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 6
- 238000007873 sieving Methods 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 230000004584 weight gain Effects 0.000 description 6
- 235000019786 weight gain Nutrition 0.000 description 6
- 108010082126 Alanine transaminase Proteins 0.000 description 5
- 208000024827 Alzheimer disease Diseases 0.000 description 5
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 5
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 5
- 239000001856 Ethyl cellulose Substances 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
- 108020004206 Gamma-glutamyltransferase Proteins 0.000 description 5
- 229920001800 Shellac Polymers 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 239000000556 agonist Substances 0.000 description 5
- 229940005529 antipsychotics Drugs 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 235000019325 ethyl cellulose Nutrition 0.000 description 5
- 229920001249 ethyl cellulose Polymers 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 102000006640 gamma-Glutamyltransferase Human genes 0.000 description 5
- 230000002093 peripheral effect Effects 0.000 description 5
- 239000004208 shellac Substances 0.000 description 5
- 229940113147 shellac Drugs 0.000 description 5
- 235000013874 shellac Nutrition 0.000 description 5
- 229940032147 starch Drugs 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 208000020925 Bipolar disease Diseases 0.000 description 4
- 206010010774 Constipation Diseases 0.000 description 4
- 206010019233 Headaches Diseases 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 229920002301 cellulose acetate Polymers 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 231100000869 headache Toxicity 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000000284 resting effect Effects 0.000 description 4
- 210000003296 saliva Anatomy 0.000 description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000001839 systemic circulation Effects 0.000 description 4
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- 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 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical class C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 206010041243 Social avoidant behaviour Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 3
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 230000003281 allosteric effect Effects 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 230000000561 anti-psychotic effect Effects 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 239000002249 anxiolytic agent Substances 0.000 description 3
- 230000000949 anxiolytic effect Effects 0.000 description 3
- 229940005530 anxiolytics Drugs 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 229940049706 benzodiazepine Drugs 0.000 description 3
- 150000001557 benzodiazepines Chemical class 0.000 description 3
- 230000036471 bradycardia Effects 0.000 description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 125000003636 chemical group Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 229940126534 drug product Drugs 0.000 description 3
- 238000002565 electrocardiography Methods 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 230000007717 exclusion Effects 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 230000037315 hyperhidrosis Effects 0.000 description 3
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000001788 irregular Effects 0.000 description 3
- 229960001375 lactose Drugs 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 231100000682 maximum tolerated dose Toxicity 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 3
- 239000000472 muscarinic agonist Substances 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000011118 polyvinyl acetate Substances 0.000 description 3
- 229920002689 polyvinyl acetate Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001671 psychotherapy Methods 0.000 description 3
- 210000001747 pupil Anatomy 0.000 description 3
- 230000000717 retained effect Effects 0.000 description 3
- 208000026451 salivation Diseases 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 229940125723 sedative agent Drugs 0.000 description 3
- 239000000932 sedative agent Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 239000003204 tranquilizing agent Substances 0.000 description 3
- 230000002936 tranquilizing effect Effects 0.000 description 3
- 239000001069 triethyl citrate Substances 0.000 description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 3
- 235000013769 triethyl citrate Nutrition 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- CVHZOJJKTDOEJC-UHFFFAOYSA-M 1,1-dioxo-1,2-benzothiazol-3-olate Chemical compound C1=CC=C2C([O-])=NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-M 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
- QGQXAMBOYWULFX-LZWSPWQCSA-N 2-morpholin-4-ylethyl (e)-6-(4,6-dihydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound OC=1C=2C(=O)OCC=2C(C)=C(O)C=1C\C=C(/C)CCC(=O)OCCN1CCOCC1 QGQXAMBOYWULFX-LZWSPWQCSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 206010001540 Akathisia Diseases 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010005885 Blunted affect Diseases 0.000 description 2
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- 102000009660 Cholinergic Receptors Human genes 0.000 description 2
- 108010009685 Cholinergic Receptors Proteins 0.000 description 2
- 206010010144 Completed suicide Diseases 0.000 description 2
- 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 2
- 208000024254 Delusional disease 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
- 206010014557 Emotional poverty Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- 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 2
- 208000009829 Lewy Body Disease Diseases 0.000 description 2
- 201000002832 Lewy body dementia Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- 208000009668 Neurobehavioral Manifestations Diseases 0.000 description 2
- 239000006057 Non-nutritive feed additive Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 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
- 102100027378 Prothrombin Human genes 0.000 description 2
- 108010094028 Prothrombin Proteins 0.000 description 2
- 208000001431 Psychomotor Agitation Diseases 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 229940121991 Serotonin and norepinephrine reuptake inhibitor Drugs 0.000 description 2
- 208000032140 Sleepiness Diseases 0.000 description 2
- 206010041349 Somnolence Diseases 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 208000001871 Tachycardia Diseases 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
- 229920001615 Tragacanth Polymers 0.000 description 2
- 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 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000003570 air Substances 0.000 description 2
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 2
- 229940063655 aluminum stearate Drugs 0.000 description 2
- 229960001301 amobarbital Drugs 0.000 description 2
- 239000003945 anionic surfactant Substances 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229940125717 barbiturate Drugs 0.000 description 2
- 235000013871 bee wax Nutrition 0.000 description 2
- 239000012166 beeswax Substances 0.000 description 2
- 238000013542 behavioral therapy Methods 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 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 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000012472 biological sample Substances 0.000 description 2
- 208000006218 bradycardia Diseases 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 229920003086 cellulose ether Polymers 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 2
- 229960001076 chlorpromazine Drugs 0.000 description 2
- 230000001149 cognitive effect Effects 0.000 description 2
- 229960000913 crospovidone Drugs 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 230000003205 diastolic effect Effects 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 208000002173 dizziness Diseases 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 208000027683 excess salivation Diseases 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229960001031 glucose Drugs 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 229940093915 gynecological organic acid Drugs 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
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 208000024714 major depressive disease Diseases 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 208000002851 paranoid schizophrenia Diseases 0.000 description 2
- 229960001412 pentobarbital Drugs 0.000 description 2
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 2
- 238000009567 person-centered psychotherapy Methods 0.000 description 2
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 2
- 229960002695 phenobarbital Drugs 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229920000139 polyethylene terephthalate Polymers 0.000 description 2
- 239000005020 polyethylene terephthalate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229920002635 polyurethane Polymers 0.000 description 2
- 239000004814 polyurethane Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 2
- 239000004800 polyvinyl chloride Substances 0.000 description 2
- 229920000915 polyvinyl chloride Polymers 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 230000001144 postural effect Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 229940039716 prothrombin Drugs 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000004626 scanning electron microscopy Methods 0.000 description 2
- 208000022610 schizoaffective disease Diseases 0.000 description 2
- 229960002060 secobarbital Drugs 0.000 description 2
- KQPKPCNLIDLUMF-UHFFFAOYSA-N secobarbital Chemical compound CCCC(C)C1(CC=C)C(=O)NC(=O)NC1=O KQPKPCNLIDLUMF-UHFFFAOYSA-N 0.000 description 2
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 2
- 238000010206 sensitivity analysis Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 230000007958 sleep Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate 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
- 239000002904 solvent Substances 0.000 description 2
- GOLXNESZZPUPJE-UHFFFAOYSA-N spiromesifen Chemical compound CC1=CC(C)=CC(C)=C1C(C(O1)=O)=C(OC(=O)CC(C)(C)C)C11CCCC1 GOLXNESZZPUPJE-UHFFFAOYSA-N 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 229960004274 stearic acid Drugs 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000006794 tachycardia Effects 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000001755 vocal effect Effects 0.000 description 2
- 229920003176 water-insoluble polymer Polymers 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- GJJFMKBJSRMPLA-HIFRSBDPSA-N (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-1-cyclopropanecarboxamide Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)N(CC)CC)C[C@@H]1CN GJJFMKBJSRMPLA-HIFRSBDPSA-N 0.000 description 1
- IGLYMJRIWWIQQE-QUOODJBBSA-N (1S,2R)-2-phenylcyclopropan-1-amine (1R,2S)-2-phenylcyclopropan-1-amine Chemical compound N[C@H]1C[C@@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 IGLYMJRIWWIQQE-QUOODJBBSA-N 0.000 description 1
- YWPHCCPCQOJSGZ-LLVKDONJSA-N (2r)-2-[(2-ethoxyphenoxy)methyl]morpholine Chemical compound CCOC1=CC=CC=C1OC[C@@H]1OCCNC1 YWPHCCPCQOJSGZ-LLVKDONJSA-N 0.000 description 1
- OMDQUFIYNPYJFM-XKDAHURESA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[[(2r,3s,4r,5s,6r)-4,5,6-trihydroxy-3-[(2s,3s,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]methoxy]oxane-3,4,5-triol 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]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@H](O)[C@H](O)O1 OMDQUFIYNPYJFM-XKDAHURESA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 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 1
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 description 1
- GBBSUAFBMRNDJC-MRXNPFEDSA-N (5R)-zopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-MRXNPFEDSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 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
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 1
- WSPOMRSOLSGNFJ-AUWJEWJLSA-N (Z)-chlorprothixene Chemical compound C1=C(Cl)C=C2C(=C/CCN(C)C)\C3=CC=CC=C3SC2=C1 WSPOMRSOLSGNFJ-AUWJEWJLSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- TWUZWTIVCCRAAD-UHFFFAOYSA-N 2-(2-butoxy-2-oxoethyl)-2-hydroxybutanedioic acid Chemical class CCCCOC(=O)CC(O)(C(O)=O)CC(O)=O TWUZWTIVCCRAAD-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
- CFVWNXQPGQOHRJ-UHFFFAOYSA-N 2-methylpropyl prop-2-enoate Chemical compound CC(C)COC(=O)C=C CFVWNXQPGQOHRJ-UHFFFAOYSA-N 0.000 description 1
- CDOUZKKFHVEKRI-UHFFFAOYSA-N 3-bromo-n-[(prop-2-enoylamino)methyl]propanamide Chemical compound BrCCC(=O)NCNC(=O)C=C CDOUZKKFHVEKRI-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
- BGBIRJIRPKZAJD-UHFFFAOYSA-N 4-ethyl-2-methylideneoctanoic acid;furan-2,5-dione Chemical compound O=C1OC(=O)C=C1.CCCCC(CC)CC(=C)C(O)=O BGBIRJIRPKZAJD-UHFFFAOYSA-N 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- XKFPYPQQHFEXRZ-UHFFFAOYSA-N 5-methyl-N'-(phenylmethyl)-3-isoxazolecarbohydrazide Chemical compound O1C(C)=CC(C(=O)NNCC=2C=CC=CC=2)=N1 XKFPYPQQHFEXRZ-UHFFFAOYSA-N 0.000 description 1
- JICJBGPOMZQUBB-UHFFFAOYSA-N 7-[(3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino]heptanoic acid Chemical compound O=S1(=O)N(C)C2=CC=CC=C2C(NCCCCCCC(O)=O)C2=CC=C(Cl)C=C21 JICJBGPOMZQUBB-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 208000007415 Anhedonia Diseases 0.000 description 1
- 206010002942 Apathy Diseases 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
- CYGODHVAJQTCBG-UHFFFAOYSA-N Bifeprunox Chemical compound C=12OC(=O)NC2=CC=CC=1N(CC1)CCN1CC(C=1)=CC=CC=1C1=CC=CC=C1 CYGODHVAJQTCBG-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920008347 Cellulose acetate propionate Polymers 0.000 description 1
- 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 1
- 229920002284 Cellulose triacetate Polymers 0.000 description 1
- 229920001661 Chitosan Chemical class 0.000 description 1
- 102000003914 Cholinesterases Human genes 0.000 description 1
- 108090000322 Cholinesterases Proteins 0.000 description 1
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 208000003870 Drug Overdose Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 208000027776 Extrapyramidal disease Diseases 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 238000000729 Fisher's exact test Methods 0.000 description 1
- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 description 1
- 108091006027 G proteins Proteins 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
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 229920000926 Galactomannan Polymers 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
- 108010068370 Glutens Proteins 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 206010018671 Grandiosity Diseases 0.000 description 1
- 206010020400 Hostility Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- ZPXSCAKFGYXMGA-UHFFFAOYSA-N Mazindol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 ZPXSCAKFGYXMGA-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 235000019886 MethocelTM Nutrition 0.000 description 1
- UEQUQVLFIPOEMF-UHFFFAOYSA-N Mianserin Chemical compound C1C2=CC=CC=C2N2CCN(C)CC2C2=CC=CC=C21 UEQUQVLFIPOEMF-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229940121743 Muscarinic receptor agonist Drugs 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- KYYIDSXMWOZKMP-UHFFFAOYSA-N O-desmethylvenlafaxine Chemical compound C1CCCCC1(O)C(CN(C)C)C1=CC=C(O)C=C1 KYYIDSXMWOZKMP-UHFFFAOYSA-N 0.000 description 1
- 206010033296 Overdoses Diseases 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 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
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical compound NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 description 1
- 229920001305 Poly(isodecyl(meth)acrylate) Polymers 0.000 description 1
- 229920002319 Poly(methyl acrylate) Polymers 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 206010036437 Posturing Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000004111 Potassium silicate Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- ZGUGWUXLJSTTMA-UHFFFAOYSA-N Promazinum Chemical compound C1=CC=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZGUGWUXLJSTTMA-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 208000008630 Sialorrhea Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- MKRNVBXERAPZOP-UHFFFAOYSA-N Starch acetate Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OC(C)=O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 MKRNVBXERAPZOP-UHFFFAOYSA-N 0.000 description 1
- 206010042008 Stereotypy Diseases 0.000 description 1
- 206010042458 Suicidal ideation Diseases 0.000 description 1
- 206010042635 Suspiciousness Diseases 0.000 description 1
- 208000032859 Synucleinopathies Diseases 0.000 description 1
- 208000034799 Tauopathies Diseases 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
- GFBKORZTTCHDGY-UWVJOHFNSA-N Thiothixene Chemical compound C12=CC(S(=O)(=O)N(C)C)=CC=C2SC2=CC=CC=C2\C1=C\CCN1CCN(C)CC1 GFBKORZTTCHDGY-UWVJOHFNSA-N 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 208000021017 Weight Gain Diseases 0.000 description 1
- 208000005946 Xerostomia Diseases 0.000 description 1
- 229920002494 Zein Polymers 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
- 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
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 208000024453 abnormal involuntary movement Diseases 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 229960002629 agomelatine Drugs 0.000 description 1
- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000012080 ambient air Substances 0.000 description 1
- 229960003036 amisulpride Drugs 0.000 description 1
- NTJOBXMMWNYJFB-UHFFFAOYSA-N amisulpride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(=O)(=O)CC)=C(N)C=C1OC NTJOBXMMWNYJFB-UHFFFAOYSA-N 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 229940095564 anhydrous calcium sulfate Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 239000003911 antiadherent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- 238000009246 art therapy Methods 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 229960005245 asenapine Drugs 0.000 description 1
- 229960002430 atomoxetine Drugs 0.000 description 1
- VHGCDTVCOLNTBX-QGZVFWFLSA-N atomoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C VHGCDTVCOLNTBX-QGZVFWFLSA-N 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229950009087 bifeprunox Drugs 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 208000025307 bipolar depression Diseases 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 229960002495 buspirone Drugs 0.000 description 1
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 description 1
- VYGAQHDGEYQIJU-UHFFFAOYSA-N butanedioic acid;phthalic acid Chemical compound OC(=O)CCC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O VYGAQHDGEYQIJU-UHFFFAOYSA-N 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000404 calcium aluminium silicate Substances 0.000 description 1
- 235000012215 calcium aluminium silicate Nutrition 0.000 description 1
- WNCYAPRTYDMSFP-UHFFFAOYSA-N calcium aluminosilicate Chemical compound [Al+3].[Al+3].[Ca+2].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O WNCYAPRTYDMSFP-UHFFFAOYSA-N 0.000 description 1
- 229940078583 calcium aluminosilicate Drugs 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 229950008138 carmellose Drugs 0.000 description 1
- 239000000679 carrageenan Chemical class 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Chemical class 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 1
- 229920006218 cellulose propionate Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 238000000546 chi-square test Methods 0.000 description 1
- 229940045110 chitosan Drugs 0.000 description 1
- 229960004782 chlordiazepoxide Drugs 0.000 description 1
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 1
- 229960001552 chlorprothixene Drugs 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- NJMYODHXAKYRHW-DVZOWYKESA-N cis-flupenthixol Chemical compound C1CN(CCO)CCN1CC\C=C\1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C2/1 NJMYODHXAKYRHW-DVZOWYKESA-N 0.000 description 1
- 229960001653 citalopram Drugs 0.000 description 1
- 229960004606 clomipramine Drugs 0.000 description 1
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 1
- 229960003120 clonazepam Drugs 0.000 description 1
- 229960004362 clorazepate Drugs 0.000 description 1
- XDDJGVMJFWAHJX-UHFFFAOYSA-M clorazepic acid anion Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(C(=O)[O-])N=C1C1=CC=CC=C1 XDDJGVMJFWAHJX-UHFFFAOYSA-M 0.000 description 1
- 229960004170 clozapine Drugs 0.000 description 1
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000009226 cognitive therapy Methods 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 229940125368 controlled substance Drugs 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 238000009223 counseling Methods 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
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- GTBGXKPAKVYEKJ-UHFFFAOYSA-N decyl 2-methylprop-2-enoate Chemical compound CCCCCCCCCCOC(=O)C(C)=C GTBGXKPAKVYEKJ-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- 229960001623 desvenlafaxine Drugs 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- GMSCBRSQMRDRCD-UHFFFAOYSA-N dodecyl 2-methylprop-2-enoate Chemical compound CCCCCCCCCCCCOC(=O)C(C)=C GMSCBRSQMRDRCD-UHFFFAOYSA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229960000394 droperidol Drugs 0.000 description 1
- RMEDXOLNCUSCGS-UHFFFAOYSA-N droperidol Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CC=C(N2C(NC3=CC=CC=C32)=O)CC1 RMEDXOLNCUSCGS-UHFFFAOYSA-N 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 231100000725 drug overdose Toxicity 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229960004341 escitalopram Drugs 0.000 description 1
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 description 1
- 229960001578 eszopiclone Drugs 0.000 description 1
- GBBSUAFBMRNDJC-INIZCTEOSA-N eszopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-INIZCTEOSA-N 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-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
- 230000005713 exacerbation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229960002419 flupentixol Drugs 0.000 description 1
- 229960002690 fluphenazine Drugs 0.000 description 1
- 229960004038 fluvoxamine Drugs 0.000 description 1
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 229910021485 fumed silica Inorganic materials 0.000 description 1
- 239000007897 gelcap Substances 0.000 description 1
- 238000009568 gestalt therapy Methods 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000021312 gluten Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical class 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- LNCPIMCVTKXXOY-UHFFFAOYSA-N hexyl 2-methylprop-2-enoate Chemical compound CCCCCCOC(=O)C(C)=C LNCPIMCVTKXXOY-UHFFFAOYSA-N 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 238000002662 humanistic therapy Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 229920003125 hypromellose 2910 Polymers 0.000 description 1
- 229940031672 hypromellose 2910 Drugs 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 230000005032 impulse control Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000266 injurious effect Effects 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
- 206010022437 insomnia Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229940125425 inverse agonist Drugs 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000013038 irreversible inhibitor Substances 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 229960002672 isocarboxazid Drugs 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 229910052743 krypton Inorganic materials 0.000 description 1
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960004391 lorazepam Drugs 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 230000014759 maintenance of location Effects 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
- 239000013521 mastic Substances 0.000 description 1
- 229960000299 mazindol Drugs 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- SLVMESMUVMCQIY-UHFFFAOYSA-N mesoridazine Chemical compound CN1CCCCC1CCN1C2=CC(S(C)=O)=CC=C2SC2=CC=CC=C21 SLVMESMUVMCQIY-UHFFFAOYSA-N 0.000 description 1
- 229960000300 mesoridazine Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VRQVVMDWGGWHTJ-CQSZACIVSA-N methotrimeprazine Chemical compound C1=CC=C2N(C[C@H](C)CN(C)C)C3=CC(OC)=CC=C3SC2=C1 VRQVVMDWGGWHTJ-CQSZACIVSA-N 0.000 description 1
- 229940042053 methotrimeprazine Drugs 0.000 description 1
- 229960003955 mianserin Drugs 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 229960000600 milnacipran Drugs 0.000 description 1
- 229940029985 mineral supplement Drugs 0.000 description 1
- 235000020786 mineral supplement Nutrition 0.000 description 1
- 229960001785 mirtazapine Drugs 0.000 description 1
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- YHXISWVBGDMDLQ-UHFFFAOYSA-N moclobemide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCCN1CCOCC1 YHXISWVBGDMDLQ-UHFFFAOYSA-N 0.000 description 1
- 229960004644 moclobemide Drugs 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000004050 mood stabilizer Substances 0.000 description 1
- 229940127237 mood stabilizer Drugs 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 238000000051 music therapy Methods 0.000 description 1
- 231100000243 mutagenic effect Toxicity 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 229940126662 negative allosteric modulator Drugs 0.000 description 1
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100001079 no serious adverse effect Toxicity 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- FSAJWMJJORKPKS-UHFFFAOYSA-N octadecyl prop-2-enoate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)C=C FSAJWMJJORKPKS-UHFFFAOYSA-N 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
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000008184 oral solid dosage form Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960001057 paliperidone Drugs 0.000 description 1
- 229940098695 palmitic acid Drugs 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229920003175 pectinic acid Chemical class 0.000 description 1
- LUALIOATIOESLM-UHFFFAOYSA-N periciazine Chemical compound C1CC(O)CCN1CCCN1C2=CC(C#N)=CC=C2SC2=CC=CC=C21 LUALIOATIOESLM-UHFFFAOYSA-N 0.000 description 1
- 229960000769 periciazine Drugs 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 229960000762 perphenazine Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 238000011422 pharmacological therapy Methods 0.000 description 1
- 229960000964 phenelzine Drugs 0.000 description 1
- QIWKUEJZZCOPFV-UHFFFAOYSA-N phenyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OC1=CC=CC=C1 QIWKUEJZZCOPFV-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000000049 pigment 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
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 229920001490 poly(butyl methacrylate) polymer Polymers 0.000 description 1
- 229920001483 poly(ethyl methacrylate) polymer Polymers 0.000 description 1
- 229920000212 poly(isobutyl acrylate) Polymers 0.000 description 1
- 229920000205 poly(isobutyl methacrylate) Polymers 0.000 description 1
- 229920000196 poly(lauryl methacrylate) Polymers 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920000184 poly(octadecyl acrylate) Polymers 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 229920000129 polyhexylmethacrylate Polymers 0.000 description 1
- 229920000197 polyisopropyl acrylate Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 229920000182 polyphenyl methacrylate Polymers 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 229940126027 positive allosteric modulator Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000019353 potassium silicate Nutrition 0.000 description 1
- 229940074415 potassium silicate Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- WIKYUJGCLQQFNW-UHFFFAOYSA-N prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 description 1
- 229960003111 prochlorperazine Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 229960003598 promazine Drugs 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- LYBIZMNPXTXVMV-UHFFFAOYSA-N propan-2-yl prop-2-enoate Chemical compound CC(C)OC(=O)C=C LYBIZMNPXTXVMV-UHFFFAOYSA-N 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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960002601 protriptyline Drugs 0.000 description 1
- BWPIARFWQZKAIA-UHFFFAOYSA-N protriptyline Chemical compound C1=CC2=CC=CC=C2C(CCCNC)C2=CC=CC=C21 BWPIARFWQZKAIA-UHFFFAOYSA-N 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 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
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 1
- 229960003770 reboxetine Drugs 0.000 description 1
- CBQGYUDMJHNJBX-RTBURBONSA-N reboxetine Chemical compound CCOC1=CC=CC=C1O[C@H](C=1C=CC=CC=1)[C@@H]1OCCNC1 CBQGYUDMJHNJBX-RTBURBONSA-N 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000013037 reversible inhibitor Substances 0.000 description 1
- 238000012552 review 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
- 238000010079 rubber tapping Methods 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 230000000698 schizophrenic effect Effects 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- 239000003775 serotonin noradrenalin reuptake inhibitor Substances 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- 239000000429 sodium aluminium silicate Substances 0.000 description 1
- 235000012217 sodium aluminium silicate Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229940100996 sodium bisulfate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940083575 sodium dodecyl sulfate Drugs 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000021058 soft food Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000000392 somatic effect Effects 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
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229960005333 tetrabenazine Drugs 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- 229960005138 tianeptine Drugs 0.000 description 1
- 229960005013 tiotixene Drugs 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 229960003741 tranylcypromine Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 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
- 229960002324 trifluoperazine Drugs 0.000 description 1
- XSCGXQMFQXDFCW-UHFFFAOYSA-N triflupromazine Chemical compound C1=C(C(F)(F)F)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 XSCGXQMFQXDFCW-UHFFFAOYSA-N 0.000 description 1
- 229960003904 triflupromazine Drugs 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- 230000036967 uncompetitive effect Effects 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229960001255 viloxazine Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 230000003936 working memory Effects 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
- HUNXMJYCHXQEGX-UHFFFAOYSA-N zaleplon Chemical compound CCN(C(C)=O)C1=CC=CC(C=2N3N=CC(=C3N=CC=2)C#N)=C1 HUNXMJYCHXQEGX-UHFFFAOYSA-N 0.000 description 1
- 229960004010 zaleplon Drugs 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical class [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 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
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
- 229960000820 zopiclone Drugs 0.000 description 1
- 229960004496 zotepine Drugs 0.000 description 1
- HDOZVRUNCMBHFH-UHFFFAOYSA-N zotepine Chemical compound CN(C)CCOC1=CC2=CC=CC=C2SC2=CC=C(Cl)C=C12 HDOZVRUNCMBHFH-UHFFFAOYSA-N 0.000 description 1
- 229960004141 zuclopenthixol Drugs 0.000 description 1
- WFPIAZLQTJBIFN-DVZOWYKESA-N zuclopenthixol Chemical compound C1CN(CCO)CCN1CC\C=C\1C2=CC(Cl)=CC=C2SC2=CC=CC=C2/1 WFPIAZLQTJBIFN-DVZOWYKESA-N 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
Definitions
- Schizophrenia affects about 0.5 to 1% of the population.
- the disease is characterized by a set of symptoms divided into positive symptoms (e.g., hallucinations, delusional thoughts, etc.), negative symptoms (e.g., social isolation, anhedonia, etc.), and cognitive symptoms (e.g., inability to process information, poor working memory, etc.).
- positive symptoms e.g., hallucinations, delusional thoughts, etc.
- negative symptoms e.g., social isolation, anhedonia, etc.
- cognitive symptoms e.g., inability to process information, poor working memory, etc.
- Patients who suffer from schizophrenia experience a major decline in quality of life. They are at increased risk for mortality due to many factors, such as an increased suicide rate.
- the cost of schizophrenia to society is high, as people living with schizophrenia are much more likely to be incarcerated, homeless, or unemployed.
- Activating the muscarinic system through muscarinic agonists may treat several diseases, such as schizophrenia, Alzheimer’s disease, Parkinson’s disease, depression, movement disorders, drug addiction, pain, and neurodegeneration, such as tauopathies or synucleinopathies.
- Muscarinic cholinergic receptors are G-protein coupled receptors with five different receptor subtypes (M1-M5), each of which is found in the CNS with different tissue distributions. Ml and M4 subtypes have been of interest as therapeutic targets for various diseases. For instance, mood stabilizers lithium and valproic acid, used for treating bipolar depression, may affect the muscarinic system, particularly through the M4 subtype receptor. Genetic evidence directly links the muscarinic system and alcohol addiction.
- compositions and methods which are meant to be exemplary and illustrative, not limiting in scope.
- one or more of the above-described problems have been reduced or eliminated, while other embodiments are directed to other improvements.
- a method of treating schizophrenia or a disease related to schizophrenia in a patient in need thereof comprising: orally administering to the patient twice daily an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof, and a plurality of trospium beads comprising a salt of trospium, via a titration scheme that comprises up-titration of the xanomeline, or a salt thereof, and the salt of trospium.
- the present disclosure further provides a method of treating acute psychosis in a patient in need thereof.
- the method comprises orally administering to the patient twice daily an oral pharmaceutical composition comprising xanomeline or a salt thereof, and a salt of trospium, to achieve at least a 10 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) score compared to placebo.
- PANSS Positive and Negative Syndrome Scale
- FIG. 1 depicts the mean ( ⁇ standard deviation) xanomeline pharmacokinetic concentrations on Day 1 for KarXT 50/20 twice-daily treatment cohort of the KAR-003 pharmacokinetic population.
- FIG. 2 depicts the mean ( ⁇ standard deviation) xanomeline pharmacokinetic concentrations by treatment on Day 3 for KarXT twice-daily treatment for all cohorts of the KAR-003 pharmacokinetic population.
- FIG. 3 depicts the mean ( ⁇ standard deviation) xanomeline pharmacokinetic concentrations by treatment on Day 7 for KarXT 100/20, 125/40, and 150/40 twice-daily treatment cohorts of the KAR-003 pharmacokinetic population.
- FIG. 4 depicts the mean ( ⁇ standard deviation) xanomeline pharmacokinetic concentrations by treatment and visit for the KAR-003 pharmacokinetic population.
- FIG. 5 depicts the mean ( ⁇ standard deviation) xanomeline pharmacokinetic trough concentrations by treatment for the KAR-003 pharmacokinetic population.
- FIG. 6 depicts the mean ( ⁇ standard deviation) trospium pharmacokinetics concentrations on Day 1 for the KarXT 50/20 twice-daily treatment cohort of the KAR-003 pharmacokinetics population.
- FIG. 7 depicts the mean ( ⁇ standard deviation) trospium pharmacokinetics concentrations by treatment on Day 3 for the KAR-003 pharmacokinetics population.
- FIG. 8 depicts the mean ( ⁇ standard deviation) trospium pharmacokinetics concentrations by treatment on Day 7 for the KAR-003 pharmacokinetics population.
- FIG. 9 depicts the mean ( ⁇ standard deviation) trospium pharmacokinetic concentrations by treatment and visit for the KAR-003 pharmacokinetic population.
- FIG. 10 depicts the mean ( ⁇ standard deviation) trospium pharmacokinetic trough concentrations by treatment and visit for the KAR-003 pharmacokinetic population.
- FIG. 11 depicts total PANSS score change from baseline (LS mean difference) of subjects in the modified intent-to-treat (mITT) population of KAR-004 Phase II study versus time in weeks (***p ⁇ 0.0001).
- FIG. 12 depicts PANSS-positive subscore change from baseline (LS mean difference) of subjects in the mITT population of KAR-004 Phase II study versus time in weeks
- FIG. 13 depicts PANSS-negative subscore change from baseline (LS mean difference) of subjects in the mITT population of KAR-004 Phase II study versus time in weeks (*p ⁇ 0.05, **p ⁇ 0.001).
- FIG. 14 depicts the PANSS Marder Factor score of subjects in the mITT population of KAR-004 Phase II study versus Visit day.
- FIG. 15 depicts the statistically significant and clinically meaningful improvement on Clinical Global Impression-Severity (CGI-S) at baseline for patients on KarXT versus placebo.
- CGI-S Clinical Global Impression-Severity
- FIG. 16 depicts the statistically significant and clinically meaningful improvement on CGI-S at the endpoint of Week 5 for patients on KarXT versus placebo.
- FIG. 17 depicts that the rates of adverse events related to muscarinic receptor agonism (nausea and vomiting) decreased over time in KarXT-treated patients.
- FIG. 18 depicts that the rates of a peripheral anticholinergic adverse event (dry mouth) decreased over time in KarXT-treated patients.
- FIG. 19 depicts a box plot of standing heart rate (beats per min, bpm) from the KarXT safety population plotted by the visit.
- FIG. 20 depicts a box plot of orthostatic heart rate (beats per min, bpm) from the KarXT safety population plotted by the visit.
- FIG. 21 depicts a box plot of orthostatic diastolic pressure (mmHg) from the KarXT safety population plotted by the visit.
- FIG. 22 depicts a box plot of the orthostatic systolic pressure (mmHg) from the KarXT safety population plotted by the visit.
- xanomeline a muscarinic receptor agonist
- the current disclosure provides a dosage form with dissolution kinetics having a more effective therapeutic effect for both active ingredients, enhanced pharmacokinetics for trospium chloride, and greater dosing compliance.
- the current disclosure also provides dosage forms with different strengths or different ratios of the two actives.
- Embodiment 1 A method of treating schizophrenia or a disease related to schizophrenia in a patient in need thereof, the method comprising: orally administering to the patient twice daily an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof, and plurality of trospium beads comprising a salt of trospium, via a titration scheme that comprises up-titration of the xanomeline, or a salt thereof, and the salt of trospium.
- Embodiment 2 A method of treating schizophrenia or a disease related to schizophrenia in a patient in need thereof, the method comprising: orally administering to the patient for at least five weeks twice daily an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof, and plurality of trospium beads comprising a salt of trospium, wherein at least one adverse event which occurred at the start of oral administration is reduced to its pretreatment level after five weeks of treatment.
- Embodiment 3 The method of Embodiment 1 or 2, wherein the administration occurs via a titration scheme that comprises up-titration of the xanomeline, or the salt thereof, and the salt of trospium until an amount equivalent to 125 mg xanomeline free base and an amount equivalent to 30 mg trospium chloride is administered twice daily.
- Embodiment 4 The method of Embodiment 1 or 2, wherein the administration occurs via a titration scheme that comprises up-titration of the xanomeline, or the salt thereof, and the salt of trospium until an amount equivalent to 150 mg xanomeline free base and an amount equivalent to 30 mg trospium chloride is administered twice daily.
- Embodiment 5 The method of Embodiment 1 or 2, wherein the administration occurs via a titration scheme that comprises up-titration of the xanomeline, or the salt thereof, and the salt of trospium until an amount equivalent to 175 mg xanomeline free base and an amount equivalent to 30 mg trospium chloride is administered twice daily.
- Embodiment 6 The method of Embodiment 1 or 2, wherein the administration occurs via a titration scheme that comprises up-titration of the xanomeline, or the salt thereof, and the salt of trospium until an amount equivalent to 175 mg xanomeline free base and an amount equivalent to 40 mg trospium chloride is administered twice daily.
- Embodiment 7 The method of any one of the proceeding Embodiments, wherein the patient has a diagnosis of schizophrenia.
- Embodiment 8 The method of any one of the proceeding Embodiments, wherein prior to administration of the oral pharmaceutical composition, the patient had a Clinical Global Impression Severity Scale (CGI-S) score of 4-7, and after administration the patient had a CGI-S score equal to 1 or 2.
- CGI-S Clinical Global Impression Severity Scale
- Embodiment 9 The method of any one of the proceeding Embodiments, wherein the xanomeline, or the salt thereof, is administered for a first period in a first amount and then the first amount is increased to a second amount.
- Embodiment 10 The method of Embodiment 9, wherein the first amount of xanomeline, or the salt thereof, is equivalent to 50 mg xanomeline free base.
- Embodiment 11 The method of Embodiment 9 or 10, wherein the first period for the xanomeline administration is between 1 and 5 days.
- Embodiment 12 The method of Embodiment 11, wherein the first period for the xanomeline administration is 2 days.
- Embodiment 13 The method of any one of Embodiments 9 to 12, wherein the second amount of xanomeline, or the salt thereof, is equivalent to 100 mg xanomeline free base.
- Embodiment 14 The method of any one of Embodiments 9 to 13, further comprising administering the xanomeline, or the salt thereof, for a second period in the second amount and then increasing the second amount to a third amount.
- Embodiment 15 The method of Embodiment 14, wherein the second period for xanomeline administration is between three days and a week.
- Embodiment 16 The method of Embodiment 14 or 15, wherein the third amount of xanomeline, or the salt thereof, is equivalent to 125 mg xanomeline free base.
- Embodiment 17 The method of any of the preceding Embodiments, wherein the salt of trospium is administered for a first time period in a first amount and the first amount is increased to a second amount.
- Embodiment 18 The method of Embodiment 17, wherein the first amount of the salt of trospium is equivalent to 20 mg trospium chloride.
- Embodiment 19 The method of Embodiment 17 or 18, wherein the first time period for trospium administration is at least a week.
- Embodiment 20 The method of any one of Embodiments 15 to 17, wherein the second amount of the salt of trospium is equivalent to 30 mg trospium chloride.
- Embodiment 21 The method of any one of the preceding Embodiments, at least one of vomiting, nausea and dry mouth which occurred at the start of oral administration is reduced to its pretreatment level after five weeks of treatment.
- Embodiment 22 The method of any one of the preceding Embodiments, wherein the xanomeline, or the salt thereof, and the salt of trospium are administered without inducing a heart rate increase of more than about 5 beats per minute.
- Embodiment 23 The method of any one of the preceding Embodiments, wherein the xanomeline, or the salt thereof, and the salt of trospium are administered without inducing syncope.
- Embodiment 24 The method of any one of the preceding Embodiments, wherein the xanomeline, or the salt thereof, and the salt of trospium are administered without inducing a change in diastolic blood pressure of more than about 5 mmHg.
- Embodiment 25 The method of any one of the preceding Embodiments, wherein the xanomeline, or the salt thereof, and the salt of trospium are administered without inducing a change in systolic blood pressure of more than about 5 mmHg.
- Embodiment 26 The method of any one of the preceding Embodiments, wherein the xanomeline, or the salt thereof, and the salt of trospium are administered without causing a severe adverse event.
- Embodiment 27 The method of any one of the preceding Embodiments, wherein the xanomeline, or the salt thereof, and the salt of trospium are administered without causing a severe adverse event related to heart rate.
- Embodiment 28 The method of any one of the preceding Embodiments, wherein the xanomeline, or the salt thereof, and the salt of trospium are administered without causing a severe adverse event related to heart rate change.
- Embodiment 29 The method of any one of the preceding Embodiments, wherein the xanomeline, or the salt thereof, and the salt of trospium are administered without causing a severe adverse event related to blood pressure.
- Embodiment 30 The method of any one of the preceding Embodiments, wherein the xanomeline, or the salt thereof, and the salt of trospium are administered without causing a severe adverse event related to blood pressure change.
- Embodiment 31 The method of any one of the preceding Embodiments, wherein the xanomeline, or the salt thereof, and the salt of trospium are administered without increasing a liver function test (LFT).
- LFT liver function test
- Embodiment 32 The method of any one of the preceding Embodiments, wherein the Positive and Negative Syndrome Scale (PANSS) total score for the patient decreases by at least 10 points compared to placebo after five weeks of treatment.
- PANSS Positive and Negative Syndrome Scale
- Embodiment 33 The method of any one of the preceding Embodiments, wherein the PANSS positive subscore decreases by at least 3 points compared to placebo after five weeks of treatment.
- Embodiment 34 The method of any one of the preceding Embodiments, wherein the PANSS negative subscore decreases by at least 2 points compared to placebo after five weeks of treatment.
- Embodiment 35 The method of any one of the preceding Embodiments, wherein the size of the xanomeline beads is between 0.425 mm and 1.18 mm.
- Embodiment 36 The method of any one of the preceding Embodiments, wherein the size of the xanomeline beads is between 0.6 mm and 0.85 mm.
- Embodiment 37 The method of any one of the preceding Embodiments, wherein the size of the trospium beads is between 0.425 mm and 1.18 mm.
- Embodiment 38 The method of any one of the preceding Embodiments, wherein the size of the trospium beads is between 0.6 mm and 0.85 mm.
- Embodiment 39 The method of any one of the preceding Embodiments, wherein the xanomeline beads contain about 2.5 times as much xanomeline free base as the trospium beads contain trospium salt.
- Embodiment 40 The method of any one of the preceding Embodiments, the plurality of xanomeline and the plurality of trospium beads having a dissolution rate of more than about 95% within about the first 45 minutes following entry of the dosage form into an aqueous solution.
- Embodiment 41 The method of Embodiment 40, having a dissolution rate of more than about 95% within about the first 20 minutes following entry of the dosage form into an aqueous solution.
- Embodiment 42 The method of any one of the preceding Embodiments, wherein the salt of xanomeline is xanomeline tartrate.
- Embodiment 43 The method of Embodiment 42, wherein the xanomeline beads comprise between 30 wt.% and 80 wt.% xanomeline tartrate.
- Embodiment 44 The method of any Embodiment 43, wherein the xanomeline beads comprise 66 wt.% xanomeline tartrate.
- Embodiment 45 The method of any one of the preceding Embodiments, wherein the xanomeline beads comprise between 15 wt.% and 65 wt.% microcrystalline cellulose.
- Embodiment 46 The method of Embodiment 45, wherein the xanomeline beads comprise 33.5 wt.% microcrystalline cellulose.
- Embodiment 47 The method of any one of the preceding Embodiments, wherein the xanomeline beads comprise between 0 wt.% and 2 wt.% talc.
- Embodiment 48 The method of Embodiment 46, wherein the xanomeline beads comprise 0.5 wt.% talc.
- Embodiment 49 The method of any one of the preceding Embodiments, wherein the xanomeline beads comprise between 30 wt.% and 80 wt.% xanomeline tartrate, between 15 wt.% and 65 wt.% microcrystalline cellulose, and between 0 wt.% and 2 wt.% talc.
- Embodiment 50 The method of Embodiment 49, wherein the xanomeline beads comprise 66 wt.% xanomeline tartrate, 33.5 wt.% microcrystalline cellulose, and 0.5 wt.% talc.
- Embodiment 51 The method of any one of the preceding Embodiments, wherein the salt of trospium is trospium chloride.
- Embodiment 52 The method of Embodiment 51, wherein the trospium beads comprise between 8 wt.% and 35 wt.% trospium chloride.
- Embodiment 53 The method of Embodiment 52, wherein the trospium beads comprise 17.7 wt.% trospium chloride.
- Embodiment 54 The method of any one of the preceding Embodiments, wherein the trospium beads comprise between 25 wt.% and 80 wt.% microcrystalline cellulose.
- Embodiment 55 The method of Embodiment 54, wherein the trospium beads comprise 46.8 wt.% microcrystalline cellulose.
- Embodiment 56 The method of any one of the preceding Embodiments, wherein the trospium beads comprise between 15 wt.% and 70 wt.% lactose monohydrate.
- Embodiment 57 The method of Embodiment 56, wherein the trospium beads comprise 35 wt.% lactose monohydrate.
- Embodiment 58 The method of any one of the preceding Embodiments, wherein the trospium beads comprise between 0 wt.% and 2 wt.% talc.
- Embodiment 59 The method of Embodiment 58, wherein the trospium beads comprise 0.5 wt.% talc.
- Embodiment 60 The method of any one of the preceding Embodiments, wherein the trospium beads comprise between 8 wt.% and 35 wt.% trospium chloride, between 25 wt.% and 80 wt.% microcrystalline cellulose, between 15 wt.% and 70 wt.% lactose monohydrate, and between 0 wt.% and 2 wt.% talc.
- Embodiment 61 The method of Embodiment 60, wherein the trospium beads comprise 17.7 wt.% trospium chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate, and 0.5 wt.% talc.
- Embodiment 62 The method of any one of the preceding Embodiments, wherein the oral pharmaceutical composition further comprises ascorbic acid.
- Embodiment 63 The method of Embodiment 62, wherein the oral pharmaceutical composition comprises between 0.2 wt.% and 1 wt.% ascorbic acid.
- Embodiment 64 The method of Embodiment 63, wherein the oral pharmaceutical composition comprises about 0.5 wt.% ascorbic acid.
- Embodiment 65 The method of any one of the preceding Embodiments, wherein the oral pharmaceutical composition further comprises butylated hydroxytoluene .
- Embodiment 66 The method of Embodiment 64, wherein the oral pharmaceutical composition comprises between 0.01 wt.% and 0.1 wt.% butylated hydroxytoluene.
- Embodiment 67 The method of Embodiment 66, wherein the oral pharmaceutical composition comprises about 0.05 wt.% butylated hydroxytoluene.
- Embodiment 68 The method of any one of the preceding Embodiments, wherein the oral pharmaceutical composition further comprises a capsule containing the plurality of xanomeline beads and the plurality of trospium beads.
- Embodiment 69 A method of treating acute psychosis in a patient in need thereof, the method comprising: orally administering to the patient twice daily an oral pharmaceutical composition comprising xanomeline or a salt thereof, and a salt of trospium, to achieve at least a 10 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) score compared to placebo.
- PANSS Positive and Negative Syndrome Scale
- Embodiment 70 The method of Embodiment 69, wherein at least an 11.6 point mean reduction in total PANNS score is achieved.
- Embodiment 71 The method of any Embodiment 69 or 70, wherein at least a 3 point mean reduction in PANSS positive subscore compared to placebo is achieved.
- Embodiment 72 The method of any one of Embodiments 69 to 71, wherein at least a 2 point reduction in the PANSS negative subscore compared to placebo is achieved.
- Embodiment 73 The method of any one of Embodiments 69 to 72, wherein the reduction in PANSS score is achieved within about 5 weeks.
- Embodiment 74 The method of any one of Embodiments 69 to 73, wherein before administration of the oral pharmaceutical composition, the patient had a Clinical Global Impression Severity Scale (CGI-S) score of 4-7, and after administration, the patient had a CGI-S score equal to 1 or 2.
- CGI-S Clinical Global Impression Severity Scale
- Embodiment 75 The method of any one of Embodiments 69 to 74, wherein the patient has a diagnosis of schizophrenia.
- Embodiment 76 The method of any one of Embodiments 69 to 75, wherein the xanomeline is xanomeline tartrate and the salt of trospium is trospium chloride.
- Embodiment 77 The method of any one of Embodiments 69 to 76, at least one adverse event which occurred at the start of oral administration is reduced to its pretreatment level after five weeks of treatment.
- Embodiment 78 The method of Embodiment 77, wherein at least one adverse event is chosen from vomiting, nausea and dry mouth.
- the articles “a” and “an” refer to one or more than one (i.e., to at least one) of the grammatical object of the article.
- an element means one element or more than one element.
- ranges set forth herein include all possible subsets of ranges and any combinations of such subset ranges.
- ranges include the stated endpoints, unless stated otherwise, where a range of values is provided, each intervening value between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure.
- the upper and lower limits of these smaller ranges may independently be included in the smaller ranges and encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both limits, ranges excluding either or both of those included limits are also contemplated to be part of the disclosure.
- wt.% is the weight percent based on the total weight, e.g., of the core, or enteric coating, or total bead, as described in context. Unless stated otherwise, the wt.% is intended to describe the weight percent based on dry weight (e.g., for a core following drying).
- controlled release is defined as a prolonged-release pattern of one or more drugs, such that the drugs are released over a period.
- a controlled release formulation has release kinetics that results in measurable serum levels of the drug over a period longer than what would be possible following intravenous injection or following administration of an immediate release oral dosage form. Controlled release, slow-release, sustained-release, extended-release, prolonged-release, and delayed-release have the same definitions.
- mammal is known in the art. Exemplary mammals include humans, primates, bovines, porcines, canines, felines, and rodents (e.g., mice and rats).
- a “patient,” “subject,” or “host” to be treated by the subject method means either a human or non-human mammal.
- pharmaceutically-acceptable carrier refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
- a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
- Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient.
- materials that may serve as pharmaceutically acceptable carriers include sugars, such as lactose, glucose, and sucrose; starches, such as com starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ring,
- salt refers to a salt prepared from relatively nontoxic acids or bases, including inorganic acids and bases and organic acids and bases, including, for example, those contained in compositions of the present disclosure.
- Suitable non-toxic acids include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, saccharinate, succinic, sulfuric, tartaric acid, p-toluenesulfonic, hydrochloric, hydrobromic, phosphoric, and sulfuric acids and the like.
- inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,
- treating is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disorder.
- therapeutic agent refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance acting locally or systemically in a subject.
- therapeutic agents also referred to as “drugs,” are described in well-known literature references such as the Merck Index (14th edition), the Physicians’ Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition).
- These therapeutic agents include without limitation medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure, or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
- psychotherapy refers to non-pharmacological therapies.
- Those skilled in the art use various techniques involving verbal and other interactions with a patient to affect a positive therapeutic outcome. Such techniques include, but are not limited to, behavior therapy, cognitive therapy, psychodynamic therapy, psychoanalytic therapy, group therapy, family counseling, art therapy, music therapy, vocational therapy, humanistic therapy, existential therapy, transpersonal therapy, client-centered therapy (also called person-centered therapy), Gestalt therapy, biofeedback therapy, rational emotive behavioral therapy, reality therapy, response-based therapy, Sandplay therapy, status dynamics therapy, hypnosis, and validation therapy.
- Psychotherapy may involve combining two or more techniques. A therapist can select and adjust the techniques based on the individual patient's needs and the patient’s response.
- muscle disorder refers to any disease or condition ameliorated by activating the muscarinic system.
- diseases include ones in which direct activation of muscarinic receptors themselves or inhibition of cholinesterase enzymes has produced a therapeutic effect.
- disorders related to schizophrenia include, but are not limited to, schizo-affective disorder, psychosis, including acute psychosis, delusional disorders, psychosis associated with Alzheimer’s disease, psychosis associated with Parkinson’s disease, psychotic depression, bipolar disorder, bipolar with psychosis, Huntington’s disease, Lewy Body dementia, or any other disease with psychotic features.
- schizo-affective disorder including acute psychosis, delusional disorders, psychosis associated with Alzheimer’s disease, psychosis associated with Parkinson’s disease, psychotic depression, bipolar disorder, bipolar with psychosis, Huntington’s disease, Lewy Body dementia, or any other disease with psychotic features.
- Psychosis refers to an abnormal condition of the mind that results in difficulties determining what is real and not.
- Symptoms of psychosis include, but are not limited to, false beliefs (delusions), seeing or hearing things that others do not see or hear (hallucinations), incoherent speech, behavior that is inappropriate for the situation, sleep problems, social withdrawal, lack of motivation, and difficulties carrying out daily activities.
- Acute psychosis refers to the quick or strong onset of psychotic symptoms in a patient, for example, as defined at “Acute and Transient Psychotic Disorder” (International Classification of Diseases- 10) and “Brief Psychosis”(DSM-IV). A sharp striking delusion with quick changes in the structure occurs in the individual who has acute psychosis after a short preliminary period of anxiety, insomnia, and confusion. Acute psychosis can include acute psychotic exacerbation, when a patient may respond to hallucinations or delusions. Acute psychosis lasts for a short time, typically from one to two weeks.
- activator means a molecule described as an agonist, partial agonist, co- agonist, physiological agonist, potentiator, stimulator, allosteric potentiator, positive allosteric modulator, allosteric agonist, or a molecule that increases the activity or signaling of receptors directly or indirectly.
- inhibitor means a molecule described as an antagonist, partial antagonist, competitive antagonist, non-competitive antagonist, uncompetitive antagonist, silent antagonist, inverse agonist, reversible antagonist, physiological antagonist, irreversible antagonist, inhibitor, reversible inhibitor, irreversible inhibitor, negative allosteric modulator, allosteric antagonist, or a molecule that decreases the activity or signaling of receptors directly or indirectly.
- an “adverse event” is any untoward medical occurrence associated with treatment with a pharmaceutical composition described herein.
- a “mild adverse event” is easily tolerated by the subject, causes minimal discomfort, and does not interfere with everyday activities.
- a “moderate adverse event” is sufficiently discomforting to interfere with everyday activities; intervention may be needed.
- a “severe adverse event” prevents everyday activities; treatment or other intervention is usually needed.
- a “serious adverse event” results in death; is life-threatening (immediate risk of death from the event as it occurred); requires or prolongs inpatient hospitalization; results in persistent or significant disability/incapacity; or results in a congenital anomaly/disability, cancer, or drug overdose.
- An adverse event is incapacitating or disabling if it results in a substantial or permanent disruption of the subject’s ability to carry out normal life functions.
- a patient is said to “tolerate” a dose of a compound if administering that dose to that patient does not result in an unacceptable adverse event or an unacceptable combination of adverse events.
- tolerance is a subjective measure and that what may be tolerable to one patient may not be tolerable to a different patient. For example, one patient may not be able to tolerate a headache. In contrast, a second patient may find headache tolerable but is not able to tolerate vomiting. For a third patient, either headache alone or vomiting alone is tolerable. Still, the patient cannot tolerate the combination of headache and vomiting, even if the severity of each is less than when experienced alone.
- maximum tolerated dose means the highest dose of a drug or therapeutic that a patient can take without the patient experiencing intolerable side effects.
- the maximum tolerated dose is typically determined empirically in clinical trials.
- muscarinic receptors refers to G-protein linked receptors that bind the neurotransmitter acetylcholine. To date, five subtypes of the muscarinic receptor have been identified. “Ml” means the subtype one muscarinic receptor. “M2” means the subtype two muscarinic receptor. “M3” means the subtype three muscarinic receptor. “M4” means the subtype four muscarinic receptor. “M5” means the subtype five muscarinic receptor.
- antipsychotic refers to a drug that diminishes psychosis, hallucinations, or delusions.
- Antipsychotics include, but are not limited to haloperidol, droperidol, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, periciazine, promazine, triflupromazine, levomepromazine, promethazine, pimozide, chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, zotepine, aripiprazole, bifeprunox, and tetrabenazine.
- anxiolytics refers to drugs that reduce anxiety, fear, panic, or related feelings.
- drugs include, but are not limited to, benzodiazepines (e.g., alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, lorazepam), buspirone, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbital), and hydroxyzine.
- anti-depressants refers to drugs that alleviate depression and related conditions (e.g., dysthymia).
- drugs include, but are not limited to, selective serotonin - reuptake inhibitors (SSRIs, e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g., desvenlafaxine, duloxetine, milnacipran, venlafaxine), mianserin, mirtazapine, norepinephrine reuptake inhibitors (e.g., atomoxetine, mazindol, reboxetine, viloxazine), bupropion, tianeptine, agomelatine, tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imi
- the terms “sedatives” or “tranquilizers” refer to drugs that induce somnolence, promote a feeling of being tired or desire to sleep, or promote a state of unconsciousness.
- drugs include, but are not limited to, benzodiazepines, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbital), eszopiclone, zaleplon, zolpidem, and zopiclone.
- an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof; and a plurality of trospium beads comprising a salt of trospium.
- the salt of trospium is chosen from trospium chloride, trospium bromide, trospium iodide, and trospium saccharinate.
- the plurality of xanomeline beads has a core comprising xanomeline or a salt thereof.
- the plurality of trospium beads has a core comprising a trospium salt.
- a capsule shell comprising hydroxypropyl methylcellulose (HPMC) containing separate populations of drug beads containing xanomeline tartrate or trospium chloride wherein the drug beads are of comparable size and release the actives rapidly and at substantially similar rates.
- HPMC hydroxypropyl methylcellulose
- the drug beads may dissolve in the stomach or pass through the pyloric valve into the duodenum intact or partially intact. Still, the two drugs' ratio, both in dissolved form and in undissolved form, remains relatively constant in the gastrointestinal tract until the drugs are absorbed.
- a capsule comprises 50 mg xanomeline as the tartrate salt and 10 mg trospium chloride. Fifty mg xanomeline as free base corresponds to about 76 mg xanomeline tartrate.
- a discrepancy in the number of drug beads in the capsule increases the probability that the drug beads' ratio would not remain substantially constant after the beads are released and disperse.
- the trospium beads are formulated with a lower drug load. Effective doses of trospium and xanomeline are contained in roughly equivalent numbers of beads.
- the trospium and xanomeline beads release at roughly similar rates.
- the percentage of xanomeline dissolved is substantially equivalent to the percentage of dissolved trospium chloride, such as at 10 min, 20 min, or 30 min.
- the medicament may also include one or more pharmaceutically acceptable salts.
- the medicament may include one or more pharmaceutically-acceptable carriers.
- the medicament may be administered orally.
- the medicament may be delivered orally using tablets, troches, liquids, emulsions, suspensions, drops, capsules, caplets or gel caps, and other methods of oral administration known to one skilled in the art.
- the medicament may be in a dosage form that immediately releases the drug.
- the medicament may have a controlled release dosage form.
- the medicament may be in dosage forms that use other controlled-release formulations known to one in the art.
- the medicament is combined with one or more therapies, including psychotherapy and drugs.
- Therapeutic agents include, but are not limited, to antipsychotics, anxiolytics, anti-depressants, sedatives, tranquilizers, analgesics, and other pharmacological interventions known to one skilled in the art.
- a therapeutic agent may fall under the category of more than one drug.
- benzodiazepines can be considered anxiolytics, sedatives, and tranquilizers.
- the bead or core can comprise one or more excipients.
- the excipients include one or more fillers, binders, and surfactants.
- Other optional ingredients include, but are not limited to, glidants, lubricants, disintegrants, swelling agents, and antioxidants.
- the xanomeline or a pharmaceutically acceptable salt thereof and the salt of trospium may be in separate matrices within the same medicament.
- the amount of xanomeline free base in the core can be at least 10 wt.% or at least 15 wt.%, or at least 20 wt.%, or at least 25 wt.%, or at least 30 wt.%.
- the amount of xanomeline tartrate can be at least 50 wt.%, or at least 55 wt.%, or at least 60 wt.%, or at least 65 wt.%, or at least 70 wt.%, or at least 75 wt.%, or at least 80 wt.%, or at least 85 wt.% of the core, in a range of about 60 wt.% to about 90 wt.% or about 65 wt.% to about 85 wt.%.
- the xanomeline beads comprise between 30 wt.% and 80 wt.% xanomeline tartrate, such as 66 wt.% xanomeline tartrate.
- the amount of trospium salt in the core can be at least 10 wt.% or at least 15 wt.%, or at least 20 wt.%, or at least 25 wt.%, or at least 30 wt.%.
- the amount of trospium chloride can be at least 50 wt.%, or at least 55 wt.%, or at least 60 wt.%, or at least 65 wt.%, or at least 70 wt.%, or at least 75 wt.%, or at least 80 wt.%, or at least 85 wt.% of the core, in a range of about 60 wt.% to about 90 wt.% or about 65 wt.% to about 85 wt.%.
- the trospium is trospium chloride.
- the trospium beads comprise between 8 wt.% and 35 wt.% trospium chloride, such as 17.7 wt.% trospium chloride.
- the matrix comprises a polymer, for example, to modify the release profile of the active in the matrix.
- the polymer comprises a water-soluble polymer.
- the water-soluble polymer is selected from EudragitTM RL, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyethylene glycol, and mixtures thereof.
- the polymer comprises a water-insoluble polymer.
- the water-insoluble polymer is selected from EudragitTM RS, ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly (ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl methyl methyl meth
- Fillers include, but are not limited to, lactose, saccharose, glucose, starch, microcrystalline cellulose, microfine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, and sodium chloride, starch, and dibasic calcium phosphate dihydrate.
- the filler is not water-soluble, although it may absorb water.
- the filler is a spheronization aid.
- Spheronization aids can include one or more of crospovidone, carrageenan, chitosan, pectinic acid, glycerides, b- cyclodextrin ( ⁇ -CD), cellulose derivatives, microcrystalline cellulose, powdered cellulose, polyplasdone crospovidone, and polyethylene oxide.
- the filler includes microcrystalline cellulose.
- the amount of filler in the xanomeline core is not particularly limited.
- the amount of filler e.g., microcrystalline cellulose
- the amount of filler can be in a range of about 10 wt.% to about 70 wt.%, or about 16 wt.% to about 23 wt.%, or at least 19 wt.% or at least 19.5 wt.%, for example about 20 wt.%.
- the xanomeline beads comprise between about 15 wt.% and about 65 wt.% microcrystalline cellulose, such as between about 15 wt.% and about 20 wt.%, between about 20 wt.% and about 25 wt.%, between about 25 wt.% and about 30 wt.%, between about 30 wt.% and about 35 wt.%, between about 35 wt.% and about 40 wt.%, between about 40 wt.% and about 45 wt.%, between about 45 wt.% and about 50 wt.%, between about 50 wt.% and about 55 wt.%, between about 55 wt.% and about 60 wt.%, or between about 60 wt.% and about 65 wt.%.
- microcrystalline cellulose such as between about 15 wt.% and about 20 wt.%, between about 20 wt.% and about 25 wt.%, between about 25 wt.% and about
- the xanomeline beads comprise 33.5 wt.% microcrystalline cellulose.
- the amount of filler in the trospium core is not particularly limited. In embodiments, the amount of filler (e.g., microcrystalline cellulose or lactose) can be in a range of about 10 wt.% to about 80 wt.%, or about 16 wt.% to about 23 wt.%, or at least 19 wt.% or at least 19.5 wt.%, for example about 20 wt.%.
- the trospium beads comprise between 25 wt.% and 80 wt.% microcrystalline cellulose, such as between about 25 wt.% and 30 wt.%, between about 30 wt.% and 35 wt.%, between about 35 wt.% and 40 wt.%, between about 40 wt.% and 45 wt.%, between about 45 wt.% and 50 wt.%, between about 50 wt.% and 55 wt.%, between about 55 wt.% and 60 wt.%, between about 60 wt.% and 65 wt.%, between about 65 wt.% and 70 wt.%, between about 70 wt.% and 75 wt.%, or between about 75 wt.% and 80 wt.%.
- microcrystalline cellulose such as between about 25 wt.% and 30 wt.%, between about 30 wt.% and 35 wt.%, between about 35 wt.% and 40
- the trospium beads comprise 46.8 wt.% microcrystalline cellulose.
- the trospium beads comprise between 15 wt.% and 70 wt.% lactose monohydrate, such as between about 15 wt.% and 20 wt.%, between about 20 wt.% and 25 wt.%, between about 25 wt.% and 30 wt.%, between about 30 wt.% and 35 wt.%, between about 35 wt.% and 40 wt.%, between about 40 wt.% and 45 wt.%, between about 45 wt.% and 50 wt.%, between about 50 wt.% and 55 wt.%, between about 55 wt.% and 60 wt.%, between about 60 wt.% and 65 wt.%, or between about 65 wt.% and 70 wt.%.
- the trospium beads comprise 35 wt.
- Binders include, but are not limited to, cellulose ethers, methylcellulose, ethylcellulose, hydroxyethylcellulose, propyl cellulose, hydroxypropyl cellulose, lower- substituted hydroxypropyl cellulose, hydroxypropylmethylcellulose (hypromellose, e.g., hypromellose 2910, MethocelTM E), carboxymethyl cellulose, starch, pregelatinized starch, acacia, tragacanth, gelatin, polyvinyl pyrrolidone (povidone), cross-linked polyvinyl pyrrolidone, sodium alginate, microcrystalline cellulose, and lower-alkyl-substituted hydroxypropyl cellulose.
- the binders are selected from wet binders.
- the binder is selected from cellulose ethers, e.g., hypromellose.
- the amount of binder in the xanomeline core is not particularly limited.
- the amount of binder e.g., hypromellose
- the amount of binder in the trospium core is not particularly limited.
- the amount of binder e.g., hypromellose
- Surfactants include, but are not limited to, anionic surfactants, including sodium lauryl sulfate, sodium deoxycholate, dioctyl sodium sulfosuccinate, and sodium stearyl fumarate, nonionic surfactants, including polyoxyethylene ethers, and polysorbate 80, and cationic surfactants, including quaternary ammonium compounds.
- the surfactant is selected from anionic surfactants, e.g., sodium lauryl sulfate.
- the amount of surfactant e.g., as a processing aid, is not particularly limited in the xanomeline core.
- the amount of surfactant e.g., microcrystalline cellulose
- the amount of surfactant, e.g., as a processing aid is not particularly limited in the trospium core.
- the amount of surfactant (e.g., sodium lauryl sulfate) can be in a range between about 0.1 wt.% and about 1 wt.%, between about 0.2 wt.% and about 0.8 wt.%, or between about 0.4 wt.% and about 0.6 wt.%, for example about 0.5 wt.%.
- Disintegrants include, but are not limited to, starch, sodium cross-linked carboxymethyl cellulose, carmellose sodium, carmellose calcium, cross-linked polyvinyl pyrrolidone, and sodium starch glycolate, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch.
- Glidants include, but are not limited to, polyethylene glycols of various molecular weights, magnesium stearate, calcium stearate, calcium silicate, fumed silicon dioxide, magnesium carbonate, magnesium lauryl sulfate, aluminum stearate, stearic acid, palmitic acid, cetanol, stearol, and talc.
- Lubricants include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, and siliconized talc.
- the xanomeline beads comprise between 0 wt.% and 2 wt.% talc, such as 0.5 wt.% talc.
- the trospium beads comprise between 0 wt.% and 2 wt.% talc, such as 0.5 wt.% talc.
- the formulation further comprises one or more antioxidants.
- antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
- water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
- oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
- the formulation comprises less than 1 wt.% antioxidant, such as 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.%, 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.% , 0.08 wt.% , 0.07 wt.% , 0.06 wt.%, 0.05 wt.%, 0.04 wt.%, 0.03 wt.%, 0.02 wt.%, or 0.01 wt.%.
- 1 wt.% antioxidant such as 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.%, 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.%
- the oral pharmaceutical composition further comprises ascorbic acid. In certain embodiments, the oral pharmaceutical composition comprises between 0.2 wt.% and 1 wt.% ascorbic acid. In certain embodiments, the oral pharmaceutical composition comprises about 0.5 wt.% ascorbic acid. In certain embodiments, the oral pharmaceutical composition further comprises butylated hydroxytoluene. In certain embodiments, the oral pharmaceutical composition comprises between 0.01 wt.% and 0.1 wt.% butylated hydroxytoluene. In certain embodiments, the oral pharmaceutical composition comprises about 0.05 wt.% butylated hydroxytoluene. In certain embodiments, the formulation comprises about 0.05 wt.% BHT or 0.5 wt.% ascorbic acid. In certain embodiments, the antioxidant is present in the xanomeline core or the xanomeline beads.
- the xanomeline beads comprise between 30 wt.% and 80 wt.% xanomeline tartrate, between 15 wt.% and 65 wt.% microcrystalline cellulose, and between 0 wt.% and 2 wt.% talc.
- the trospium beads comprise between 0.2 wt.% and 2 wt.% talc, such as 0.5 wt.% talc.
- the trospium beads comprise between 8 wt.% and 35 wt.% trospium chloride, between 25 wt.% and 80 wt.% microcrystalline cellulose, between 15 wt.% and 70 wt.% lactose monohydrate, and between 0.2 wt.% and 2 wt.% talc.
- the xanomeline tartrate drug beads comprise 66 wt.% xanomeline tartrate, 33.5 wt.% microcrystalline cellulose and 0.5 wt.% talc.
- the trospium chloride beads comprise 17.7 wt.% trospium chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate, and 0.5 wt.% talc.
- the xanomeline tartrate beads contain about 2.5 times as much xanomeline as the trospium chloride beads contain trospium chloride.
- capsules can be prepared with different amounts of xanomeline tartrate and trospium chloride beads.
- capsules contain 25 mg xanomeline and 10 mg trospium chloride, 50 mg xanomeline and 10 mg trospium chloride, 50 mg xanomeline and 20 mg trospium chloride, 75 mg xanomeline and 10 mg trospium chloride, 75 mg xanomeline and 20 mg trospium chloride, 125 mg xanomeline and 30 mg trospium chloride, or 125 mg xanomeline and 40 mg trospium chloride.
- the capsule contains 25 mg xanomeline as xanomeline tartrate and 10 mg trospium chloride.
- the capsule contains 50 mg xanomeline as xanomeline tartrate and 10 mg trospium chloride. In certain embodiments, the capsule contains 50 mg xanomeline as xanomeline tartrate and 20 mg trospium chloride. In certain embodiments, the capsule contains 75 mg xanomeline as xanomeline tartrate and 10 mg trospium chloride. In certain embodiments, the capsule contains 75 mg xanomeline as xanomeline tartrate and 20 mg trospium chloride. In certain embodiments, the capsule contains 125 mg xanomeline as xanomeline tartrate and 20 mg trospium chloride.
- the capsule contains 125 mg xanomeline as xanomeline tartrate and 40 mg trospium chloride. In certain embodiments, the capsule contains 150 mg xanomeline and 20 mg trospium chloride. In certain embodiments, the capsule contains 150 mg xanomeline and 30 mg trospium chloride. In certain embodiments, the capsule contains 150 mg xanomeline and 40 mg trospium chloride. In certain embodiments, the capsule contains 175 mg xanomeline and 20 mg trospium chloride. In certain embodiments, the capsule contains 175 mg xanomeline and 30 mg trospium chloride. In certain embodiments, the capsule contains 175 mg xanomeline and 40 mg trospium chloride.
- the medicament contains from five milligrams to 700 milligrams of xanomeline. In an embodiment, the medicament contains from 25 milligrams to 300 milligrams of xanomeline.
- the medicament contains from one milligram to 400 milligrams of trospium chloride. In an embodiment, the medicament contains from 6.5 milligrams to 200 milligrams of trospium chloride.
- trospium chloride extended-release is used as the trospium chloride in the medicament.
- the medicament contains from one milligram to 400 milligrams of trospium chloride extended-release.
- the medicament contains from 6.5 milligrams to 200 milligrams of trospium chloride extended- release.
- the medicament contains 75 mg or 225 milligrams of xanomeline, and the same medicament contains 20 mg or 40 milligrams of trospium chloride. In another embodiment, the medicament contains 75 mg or 225 milligrams of xanomeline, and a different medicament to be co-administered contains 20 mg or 40 milligrams of trospium chloride.
- the beads may be coated with functional or non-functional coatings, such as aesthetic, handling, or stability.
- the beads might be coated with a pH-sensitive coating so that they do not dissolve in the low pH of the stomach.
- a nonfunctional coating might be used to maintain chemical separation between the beads or for cosmetic reasons.
- the controlled release formulation comprises a semi- permeable coating.
- the xanomeline and trospium chloride may be in different coatings in the same formulation.
- the xanomeline and trospium chloride can be in different coatings in different formulations or dosing vehicles.
- the semi -permeable coating comprises a polymer.
- the controlled release formulation comprises a matrix that suspends the xanomeline and trospium chloride.
- the distribution of coating thicknesses can be stated in the weight gain of coating material based on the total weight of the coated beads.
- the distribution of coating thicknesses is at least 2% based on the total weight of the coated beads.
- the distribution of coating thicknesses is at least 3%.
- the distribution of coating thicknesses is at least 4%.
- the distribution of coating thicknesses is at least 5%.
- the distribution of coating thicknesses is at least 6%.
- the distribution of coating thicknesses is at least 7%.
- the distribution of coating thicknesses is at least 8%.
- the distribution of coating thicknesses is at least 9%.
- the distribution of coating thicknesses is at least 10%. In another embodiment, the distribution of coating thicknesses is at least 11%. In another embodiment, the distribution of coating thicknesses is at least 12%. In another embodiment, the distribution of coating thicknesses is at least 13%. In another embodiment, the distribution of coating thicknesses is at least 14%.
- the difference in coating thickness from bead to bead can be in a range of +/- 1-7% based on the coated beads' total weight.
- the distribution of coating thicknesses can between about 2% and about 14% based on the weight of the coated beads, such as between about 3% and about 13%, between about 4% and about 12%, between about 5% and about 11%, between about 6% to about 10%, between about 7% and 9%, between about 3% and 14%, between about 4% and 14%, between about 4% and 13%, or between 4% and about 12%.
- the absorption (area under the curve, AUC) of the dosage form when dosed orally is advantageously increased, compared to other dosage forms of xanomeline or trospium chloride.
- AUC area under the curve
- the increase in absorption is influenced by the dosage form exhibiting a pseudo-extended release profile.
- the pseudo-extended release profile is influenced by one or more factors, including distribution of coating thicknesses when present, distribution of bead particle sizes, and the beads having irregular bead shapes.
- the coating completely dissolves at the trigger pH relatively quickly to release the xanomeline and/or trospium chloride compositions, whereas for beads having a relatively thick coating the coating takes somewhat longer to completely dissolve and release the xanomeline and/or trospium chloride compositions.
- the gut transit time of the beads could be varied due to bead size and/or shape, such that the transit time until reaching the coating dissolution pH is varied, thus contributing to a pseudo-extended release profile.
- the dosage form exhibits substantially equivalent (e.g., bioequivalent) C max and/or AUC characteristics when administered orally inside a capsule shell or without a capsule shell.
- the dosage form provides a progressive and predictable absorption curve.
- the T max of the dosage form when dosed orally, is more stable on a dose-to-dose basis because the beads are individually coated.
- a predictable, consistent T max is advantageous for accomplishing a more consistent, sustained therapeutic effect.
- process-related variations in coating thickness or other influences on coating dissolution affect only a fraction of the xanomeline and trospium chloride in the dosage form. They tend to lead to pseudo-extended release behavior.
- coated capsules comprising xanomeline and trospium chloride microspheres exhibit significant variability in absorption time from the capsule to capsule.
- the oral pharmaceutical composition comprises xanomeline and/or a salt thereof and trospium chloride for treating a muscarinic disorder in a patient in need thereof, which when administered to the patient in need thereof, the composition is sufficient to provide an in-vivo plasma profile comprising a median T max for xanomeline of 2 hours and a median T max for trospium of 1 hour.
- the in-vivo plasma profile further comprises a mean dose-normalized C max of between 48.5 and 121.3 pg/mL/mg.
- the in-vivo plasma profile further comprises a mean dose-normalized C max of trospium of between 156 and 375 pg/mL/mg.
- the in-vivo plasma profile further comprises a mean dose-normalized AUC 0-12 of xanomeline of between 263 and 577 hr pg/mL/mg. In certain embodiments, the in-vivo plasma profile further comprises a mean dose-normalized AUC 0-12 of trospium of between 881 and 2024 hr ⁇ pg/mL/mg. In certain embodiments, the in-vivo plasma profile further comprises a mean C max of trospium at 7850 ⁇ 3360 pg/mL. In certain embodiments, the in- vivo plasma profile further comprises a mean AUC 0-12 of 41900 ⁇ 15500 hr pg/mL.
- the dosage form exhibits advantageous storage stability, e.g., measured by the amount of xanomeline present following storage and/or by the total amount of related substances.
- the storage stability can be assessed following storage at typical ambient conditions (e.g., 25 °C and 60% relative humidity) or accelerated stability conditions involving increased temperature and/or humidity.
- the dosage form and methods are contemplated to include embodiments of any combination of one or more of the additional optional elements, features, and steps further described below (including those shown in the figures and Examples) unless stated otherwise.
- Reference to a bead and properties thereof apply equally to a collection of beads (e.g., a plurality of such beads).
- referring to a core and properties thereof apply equally to a collection of cores (e.g., a plurality of such cores).
- the enteric (gastro-resistant) coating material e.g., polymer
- the enteric (gastro-resistant) coating material can be one that will dissolve in intestinal juices at a pH level higher than that of the stomach, e.g., a pH of greater than 4.5, such as within the small intestine, and therefore permit the release of the active substance in the regions of the small intestine and substantially not in the upper portion of the GI tract.
- the enteric material begins to dissolve in an aqueous solution at pH between about 4.5 and about 5.5.
- the enteric material rapidly dissolves in an aqueous solution at a pH of about 5.
- the enteric material rapidly dissolves in an aqueous solution at a pH of about 5.5.
- pH-sensitive materials do not significantly dissolve until the dosage form has emptied from the stomach.
- the small intestine's pH gradually increases from about 4.5 to about 6.5 in the duodenal bulb to about 7.2 in the distal portions of the small intestine (ileum).
- the coating should begin to dissolve within the pH range of the duodenum and continue to dissolve at the pH range within the small intestine. Therefore, the amount (thickness) of enteric coating should be substantially dissolved during the about three-hour transit time within the small intestine (e.g., the proximal and mid-small intestine).
- Suitable enteric (gastro-resistant) materials include, but are not limited to, cross- linked polyvinyl pyrrolidone; non-crosslinked polyvinylpyrrolidone; hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate succinate; cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate trimellitate; starch acetate phthalate; polyvinyl acetate phthalate; carboxymethyl cellulose; methyl cellulose phthalate; methyl cellulose succinate; methyl cellulose phthalate succinate; methyl cellulose phthalic acid half ester; ethyl cellulose succinate; carboxymethylamide; potassium methacrylate divinylbenzene copolymer; polyvinyl alcohols; polyoxyethylene glycols; polyethylene glycol; sodium alginate; galactomannan; carboxypolymethylene; sodium carboxymethyl starch
- EudragitTM -L and -S series including L 100-55, L 30 D-55, L 100, S 100, L 12.5, and S 12.5, available from Evonik Industries; polyvinyl acetate; fats; oils; waxes; fatty alcohols; shellac; zein; gluten; ethylacrylate-maleic acid anhydride copolymer; maleic acid anhydride- vinyl methyl ether copolymer; styrol- maleic acid copolymer; 2-ethyl-hexyl-acrylate maleic acid anhydride; crotonic acid- vinyl acetate copolymer; glutaminic acid/glutamic acid ester copolymer; carboxymethylethylcellulose glycerol monooctanoate; polyarginine; poly(ethylene); poly(propylene); poly(ethylene oxide); poly(ethylene terephthalate); poly(vinyl isobutyl ether); poly(vinyl chloride); and polyurethane.
- enteric materials may also be used.
- the enteric material rapidly dissolves at pH 5.5 and higher to provide fast dissolution in the upper bowel.
- the enteric material can be selected from a copolymer of methacrylic acid and methyl methacrylate and a copolymer of methacrylic acid and ethyl acrylate.
- an enteric polymer is poly(methacrylic acid co-ethyl acrylate)l:l (EudragitTM L 30 D-55 and EudragitTM L 100-55).
- enteric coating coatings include beeswax and glyceryl monostearate; beeswax, shellac and cellulose; and cetyl alcohol, mastic and shellac, and shellac and stearic acid; polyvinyl acetate and ethyl cellulose; and a neutral copolymer of polymethacrylic acid esters (EudragitTM L 30D); copolymers of methacrylic acid and methacrylic acid methylester, or a neutral copolymer of polymethacrylic acid esters containing metallic stearates.
- Such coatings comprise mixtures of fats and fatty acids, shellac and shellac derivatives, and the cellulose acid phthalates, e.g., those with free carboxyl content.
- plasticizers can be added to enteric polymers to increase their pliability and reduce brittleness, as known in the art.
- Suitable plasticizers include, for example, butyl citrates, triethyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycols (PEGs, such as PEG 6000), acetyl triethyl citrate, and triacetin.
- the plasticizer is triethyl citrate.
- plasticizers While some enteric materials are flexible and do not require plasticizers, more brittle polymers (e.g., EudragitTM L/S types, EudragitTM RL/RS, and EudragitTM FS 30 D) benefit from plasticizers, for example, ranging from between 5 wt.% and 30 wt.% based on the dry polymer mass, between about 8 wt.% and about 12 wt.% triethyl citrate with poly(methacrylic acid co-ethyl acrylate) 1:1.
- plasticizers for example, ranging from between 5 wt.% and 30 wt.% based on the dry polymer mass, between about 8 wt.% and about 12 wt.% triethyl citrate with poly(methacrylic acid co-ethyl acrylate) 1:1.
- the enteric coatings comprise one or more anti-tacking agents (antiadherents) to reduce the film's tackiness and prevent agglomeration, as it is known in the art.
- anti-tacking agents include, but are not limited to, talc, glyceryl monostearate, fumed silica (e.g., AerosilTM 200), precipitated silica (e.g., SipernatTM PQ), and magnesium stearate.
- Anti-tacking agents can be used in any suitable quantity, for example ranging between about 10 wt.% and 100 wt.% based on dry polymer mass, between about 10 wt.% and about 50 wt.%, between about 10 wt.% and about 30 wt. %, or between about 15 wt.% and about 30 wt.%. For example, in one embodiment in ranges between 15 wt.% and about 30 wt.% based on dry polymer mass.
- One or more surfactants can also be added to an enteric coating mixture to increase substrate wettability and/or stabilize suspensions, as it is known in the art.
- Surfactants include Polysorbate 80, sorbitan monooleate, and sodium dodecyl sulfate, and other surfactants described herein.
- any suitable process can form the enteric coating.
- Coating processes include pan coating, fluid bed coating, and dry coating (e.g., heat dry coating and electrostatic dry coating).
- Pan coating and fluid bed coating using solvent are well-established processes.
- the enteric material and optional excipients e.g., pigments, plasticizers, anti- tacking agents
- the coating solution or dispersion is sprayed into solid dosage forms in a pan coater or a fluid bed dryer and dried by hot air.
- the coating fluid is sprayed from the fluid bed apparatus's bottom.
- the coating fluid is applied by top spraying.
- a tangential spray is applied.
- the amount of enteric material applied is sufficient to achieve the desired acid resistance and release characteristics.
- the amount of enteric coating meets USP ⁇ 711> requirements (USP 36-NF 31) for delayed-release dosage forms, thereby not releasing 10.0 wt.% of the drug after 2 hours in 0.1 N HC1.
- the formulation releases at least 80% of the active in 20 minutes in pH 6.8 buffer solution, e.g., using a dissolution method of USP 36-NF 31 section ⁇ 711>.
- the enteric coating is present in an amount in a range between about 10% and 40%, or between 25% and about 35% as measured by the weight gain compared to the uncoated particle cores, or ranging between about 25% and about 31% weight gain, between about 27% and about 31% weight gain, or between about 28.5% and about 31% weight gain, based on the weight of the uncoated particle cores.
- the formulation can include a capsule shell in which the beads are disposed.
- Soft and hard capsule shells are known.
- the capsule shell is a hard-capsule shell in one embodiment, e.g., a gelatin capsule shell or a vegetable-based hard capsule shell.
- the capsule shell comprises one or more enteric coatings described herein. During accelerated storage, gelatin capsules may collapse.
- the formulation can include a hydroxypropyl methylcellulose capsule shell.
- one embodiment combining various of the features described above includes a pharmaceutical dosage form comprising a plurality of xanomeline beads, the beads comprising a core comprising xanomeline tartrate, a filler (optionally microcrystalline cellulose), a binder (optionally hypromellose), and an enteric coating (optionally EudragitTM
- the plurality of beads has a distribution of particle sizes ranging between about 0.7 mm and about 2.5 mm, wherein the enteric coating ranges between about 20% and about 40% based on the weight of the bead cores, and wherein the beads are disposed in a capsule shell.
- the plurality of beads has a distribution of particle sizes.
- the plurality of beads has bead shapes.
- the plurality of beads has a distribution of coating thicknesses when present.
- Beads having a distribution of particle sizes were shown to exhibit advantageous pharmacokinetics. Without intending to be bound by any theory, it is contemplated that the pharmacokinetics are influenced by the plurality of beads having a distribution of core sizes.
- the particle sizes of the beads range between about 0.4 mm and about 1.2 mm, such as between about 0.4 mm and about 0.5 mm, between about 0.5 mm and about 0.6 mm, between about 0.6 mm and about 0.7 mm, between about 0.7 mm and about 0.8 mm, between about 0.8 mm and about 0.9 mm, between about 0.9 mm and about 1.0 mm, between about 1.0 mm and about 1.1 mm, or between about 1.1 mm and about 1.2 mm.
- the size of the xanomeline beads is between about 0.425 mm and about 1.18 mm.
- the size of the xanomeline beads is between about 0.6 mm and about 0.85 mm. In certain embodiments, the size of the trospium beads is between about 0.425 mm and about 1.18 mm. In certain embodiments, the size of the trospium beads is between about 0.6 mm and about 0.85 mm.
- the beads or bead mixtures may be used, for example, in suspensions, filled into capsules, compressed into tablets, or filled into sachets. One or more types of modified release beads can be mixed and encapsulated or used as a sprinkle on the subject’s food. In certain embodiments, the oral solid dosage form may be any of these forms. In certain embodiments, the dosage form is a capsule.
- the particle size of the beads becomes too small, the variability in the content of the active increases. As the particle size becomes too large, the beads are too large for drug products labeled to be administered via sprinkling (e.g., on applesauce or other soft foods, such as jellies) and swallowed without chewing or administered via an enteral feeding tube. Also, as the particle size increases, the larger particles get coated more than the smaller particles, resulting in lower relative assay than smaller particles. Relatively more beads are needed to meet the label strength per capsule. Filling a capsule shell with enough large particles to meet the label strength per capsule becomes difficult or impossible (e.g., to fill a size 0 capsule to a 75-mg strength of xanomeline free base).
- the beads are formulated into capsules, e.g., with an encapsulation machine.
- Various capsule sizes may accommodate the strength and fill weight of the target formulations. Capsule size ranges from 00 to 5 for fill weights ranging between about 15 mg and about 630 mg.
- the beads can be sorted (e.g., via sieving) to the desired particle size.
- the particle size range is any particle size range or combination described above regarding the cores.
- the particle size range is the same as the particle size range of the uncoated cores.
- the beads can be sieved such that 5% or less of the bead cores by weight is retained on a #12 mesh (1.68 mm) screen, and 10% or less by weight pass through a #20 mesh (0.84 mm) screen.
- a method for preparing an oral pharmaceutical composition comprising admixing beads comprising a plurality of xanomeline beads comprising xanomeline or a pharmaceutically acceptable salt thereof with a plurality of trospium beads comprising a salt of trospium, such as trospium chloride.
- the method further comprises formulating the admixed beads into capsules.
- Also disclosed herein are a method for preparing the dosage form comprising coating a core comprising xanomeline or a pharmaceutically acceptable salt thereof and an excipient with an enteric polymer to form the enteric coating, and coating a core comprising trospium chloride or a pharmaceutically acceptable salt thereof and an excipient with an enteric polymer to form the enteric coating.
- the core can be formed by a wet granulation method.
- drug beads are sorted (e.g., via sieving) to a desired particle size range before enteric coating, and optionally again following enteric coating.
- the drug beads may be made by different processes, including, but not limited to, spheronizing an extruded wet mass and coating of inert core spheres in a fluidized bed.
- the beads are prepared by extrusion and spheronization.
- the beads are formulated to flow freely and to be compatible with modern encapsulation equipment.
- the beads are blended to form a uniform mixture filled into capsules in a single stage.
- the beads are filled separately into capsules using a two-stage capsule filler.
- any suitable process can form the cores comprising xanomeline or pharmaceutically acceptable salts thereof.
- the core is formed by granulating a mixture of xanomeline or a pharmaceutically acceptable salt thereof with an excipient and milling to a desired particle size range.
- the core can be formed by extrusion and spheronization of a mixture of xanomeline or a pharmaceutically acceptable salt thereof with an excipient.
- any suitable process can form the cores comprising trospium chloride or pharmaceutically acceptable salts thereof.
- the core is formed by granulating a mixture of trospium chloride or a pharmaceutically acceptable salt thereof with an excipient and milling to a desired particle size range.
- the core can be formed by extrusion and spheronization of a mixture of trospium chloride or a pharmaceutically acceptable salt thereof with an excipient.
- Granulating processes can include fluid bed granulation, wet granulation, hot melt granulation, and spray congealing. Other processes include slugging and roller compaction.
- the mixtures to be granulated can first be dry -blended.
- the dry -blended dry ingredients can be mixed with water before extrusion.
- Extrusion and spheronization of a mixture of xanomeline or a pharmaceutically acceptable salt thereof and trospium chloride with an excipient provide desirable cores with a distribution of particle sizes as described herein and one or more other desirable properties.
- short processing times can lead to a more stable product. For example, reducing spheronization reduces friction and related heat, reducing the time the product is exposed to air (either when moist and/or before packaging) diminishes oxidation.
- rapid processing by extrusion and spheronization can lead to a poor-quality product, such as having a large fraction of the bead cores falling outside a desired particle size range.
- the moisture absorbed by spheronization aids influences the beads' spheronization characteristics.
- the moisture content of the granulation mixture, before drying ranging between about 20 wt.% and about 40 wt.%, such as between 25 wt.% and about 35 wt.%, between about 28 wt.% and about 32 wt.%, at least about 28 wt.%, at least about 28.5, between about 20 wt.% and about 40 wt.%, between about 25 wt.% and about 35 wt.%, between about 27 wt.% and about 31 wt.%, or between about 28.5 wt.% and about 31 wt.%.
- the wet mass can be held before extrusion, allowing the spheronization aid to swell with granulating fluid.
- the hold time can be at least 15 minutes, such as at least 30 minutes, at least 45 minutes, or at least 60 minutes. In certain embodiments, the hold time ranges between about 15 minutes and about 120 minutes, such as between 30 and 100 minutes or between 60 and 90 minutes.
- the method can include a step of sorting (e.g., by sieving) the cores before optional coating to retain particles in a predetermined size range, for example, sizes ranging between about 0.7 mm and about 2.8 mm, such as between about 0.7 mm and about 2.5 mm, between about 0.8 mm and about 1.7 mm, or any range described herein.
- a predetermined size range for example, sizes ranging between about 0.7 mm and about 2.8 mm, such as between about 0.7 mm and about 2.5 mm, between about 0.8 mm and about 1.7 mm, or any range described herein.
- the method can include a step of sorting (e.g., by sieving) the beads after optional coating to retain particles in a size range, for example, sizes ranging between about 0.7 mm and about 2.8 mm, such as between about 0.7 mm and about 2.5 mm, or between about 0.8 mm and about 1.7 mm, or any range described herein.
- a step of sorting e.g., by sieving
- Water can be a granulation agent.
- Microcrystalline cellulose can be in the cores as a spheronization aid.
- Hypromellose can be included in the cores as a binder.
- the extrusion screen size can be 1.0 mm.
- the friction plate of the spheronizer can be cross-hatched.
- the friction plate of the spheronizer can be cross-hatched with a square pitch of at least about 3 mm, or greater than about 3 mm, or at least about 4 mm, or greater than about 4 mm, or ranging between about 3 mm and about 7 mm, or about 5 mm.
- the spheronization time can be less than about 5 minutes, or less than about 4 minutes, or less than about 3 minutes, or less than about 2 minutes, or up to 1 minute.
- the spheronized particles can include non-spherical particles (i.e., irregular shapes), for example, a substantial fraction thereof, such as at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, or at least about 70 wt.% thereof.
- non-spherical particles i.e., irregular shapes
- the pharmaceutical composition is stored with a desiccant, for example, pharmaceutical grades of silica gel, crystalline sodium, potassium or calcium aluminosilicate, colloidal silica, anhydrous calcium sulfate, and the like.
- a desiccant for example, pharmaceutical grades of silica gel, crystalline sodium, potassium or calcium aluminosilicate, colloidal silica, anhydrous calcium sulfate, and the like.
- the pharmaceutical composition is stored with an oxygen absorber.
- the pharmaceutical composition is stored under a dry inert gas such as nitrogen, helium, argon, neon, xenon, krypton, or a mixture thereof.
- a dry inert gas such as nitrogen, helium, argon, neon, xenon, krypton, or a mixture thereof.
- the pharmaceutical composition is stored under reduced pressure compared to the external ambient air.
- the pharmaceutical composition is stored at a reduced temperature, e.g., at refrigerated temperatures (e.g., 2 °C to 8 °C). In certain embodiments, the pharmaceutical composition is stored in such a manner have fewer impurities, such as Impurity A, than when stored at 25 °C.
- the pharmaceutical composition is stored by a manufacturer, a distributor, a pharmacy, or a hospital at a temperature of between about 2 °C and about 8 °C before dispensing the oral pharmaceutical composition to the subject.
- the pharmaceutical composition is stored at a temperature of between about 20 °C and about 25 °C.
- a method for preparing a pharmaceutical dosage form comprising xanomeline beads comprises forming a wet mass comprising xanomeline tartrate and an excipient, optionally microcrystalline cellulose, with a moisture content ranging between about 20 wt.% and about 40 wt.%, extruding and spheronizing the wet mass comprising xanomeline tartrate and excipient to make cores, sorting the cores to a target particle size range, optionally between about 0.7 mm and about 2.5 mm, coating the sorted cores with a polymer to form beads comprising a core and a coating, and sorting the bead particles to a target particle size range, optionally between about 0.7 mm and about 2.5 mm.
- a method for preparing a pharmaceutical dosage form comprising trospium beads comprises forming a wet mass comprising trospium chloride and an excipient, optionally microcrystalline cellulose, with a moisture content ranging between about 20 wt.% and about 40 wt.%, extruding, spheronizing, and drying the wet mass comprising trospium chloride and excipient to make cores, sorting the cores to a target particle size range, optionally between about 0.7 mm and about 2.5 mm, coating the sorted cores with a polymer to form beads comprising a core and a coating, and sorting the bead particles to a target particle size range, optionally between about 0.7 mm and about 2.5 mm.
- a pharmaceutical composition comprising xanomeline and/or a salt thereof and less than 0.5 wt.% 3-[(4-hexyloxy)-l,2,5-thiadizaol-3-yl]-5-hydroyl-1- methylpyridin-1-ium (Impurity A).
- the pharmaceutical composition comprises less than 0.30 wt.% of Impurity A, such as less than 0.25 wt.%, less than 0.20 wt.%, less than 0.15 wt.%, less than 0.14 wt.% or less than 0.1 wt.%.
- composition comprising xanomeline and/or a salt thereof and less than 0.15 wt.% 3-[(4-hexyloxy)-l,2,5-thiadizaol-3-yl]-5-hydroyl-1-methylpyridin-1-ium (Impurity A).
- an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and less than 0.5 wt.% 3-[(4- hexyloxy)-l,2,5-thiadizaol-3-yl]-5-hydroyl-1-methylpyridin-1-ium; and a plurality of trospium beads comprising a salt of trospium.
- an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and less than 0.15 wt.% 3-[(4-hexyloxy)-l,2,5-thiadizaol-3-yl]-5-hydroyl-1- methylpyridin-1-ium; and a plurality of trospium beads comprising a salt of trospium.
- the pharmaceutical composition comprises less than 0.5 wt.% of Impurity A after the pharmaceutical composition is stored for at least 3 months at 40 °C and 75% relative humidity.
- the total impurities in the pharmaceutical compositions provided herein are no greater than about 5% by weight, no greater than about 4% by weight, no greater than about 3% by weight, no greater than about 2.5% by weight, no greater than about 2% by weight, no greater than about 1.5% by weight, no greater than about 1% by weight, no greater than about 0.5% by weight, or no greater than about 0.1% by weight.
- a method of activating muscarinic receptors in a biological sample comprising contacting the biological sample with any oral pharmaceutical composition described herein.
- a method for treating a disorder ameliorated by activating muscarinic receptors in a subject in need thereof comprising administering to the subject in need thereof any oral pharmaceutical composition described herein.
- the tolerability of xanomeline, a muscarinic activator, is increased by co- administering trospium chloride, a muscarinic antagonist.
- the most common adverse events observed with administering xanomeline are nausea, vomiting, diarrhea, excessive sweating, and excessive salivation (so-called cholinergic adverse events).
- a common anticholinergic adverse event observed with administering trospium chloride is dry mouth (xerostomia).
- the disclosed compositions reduced the incidence of these adverse events in humans, evincing increased xanomeline tolerability.
- the occurrence of a cholinergic or anticholinergic adverse event is not statistically distinguishable from a placebo control.
- xanomeline combined with trospium chloride treats an animal.
- the animal is a mammal.
- the mammal is a human being.
- trospium chloride decreases the side effects associated with xanomeline.
- side effects include, but are not limited to, GI side effects, cardiac side effects, excessive sweating, and excessive salivation.
- the use of trospium with xanomeline allows the xanomeline to be used clinically when the xanomeline would not otherwise be used clinically due to its side effects.
- the use of trospium chloride with the xanomeline allows for the xanomeline to achieve a higher maximum tolerated dose than xanomeline would otherwise achieve.
- animal models demonstrate the efficacy of new therapeutics for schizophrenia, including pharmacological models (e.g., ketamine model) and genetic models (e.g., DISCI mouse).
- pharmacological models e.g., ketamine model
- genetic models e.g., DISCI mouse
- animal models including rodents, dogs, and non-human primates, demonstrate the side effect profile of pharmacological agents.
- Animal models are an experimental proxy for humans but may suffer from deficiencies in the physiological differences between humans and animals and may have limited predictive power for human experiments, particularly for central nervous system disorders.
- the disclosed combination can be tried in controlled clinical trials of people.
- Standard measures based on patient self-report can be used by those skilled in the art to assess various side effects such as GI discomfort.
- objective physiological measures e.g., EKGs
- a set of standard measures has also been developed to assess schizophrenia symptoms, including the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression (CGI).
- BPRS Brief Psychiatric Rating Scale
- PANSS Positive and Negative Syndrome Scale
- CGI Clinical Global Impression
- clinical trials are double-blinded, where one group of patients receives an inactive placebo, and the other group the active intervention.
- the Positive and Negative Syndrome Scale is a medical scale used for measuring symptom severity of patients with schizophrenia.
- the name refers to the two types of symptoms in schizophrenia, as defined by the American Psychiatric Association: positive symptoms, which refer to an excess or distortion of normal functions (e.g., hallucinations and delusions), and negative symptoms, which represent a diminution or loss of normal functions. Some of these functions which may be lost include normal thoughts, actions, the ability to tell generies from reality, and the ability to properly express emotions [0242]
- the PANSS is a relatively brief interview of about 45 to 50 minutes. The interviewer must be trained to a standardized level of reliability. The patient is rated from 1 to 7 on 30 different symptoms in three categories based on the interview and reports of family members or primary care hospital workers.
- PANSS Marder factor score is the sum of five negative scales and two general scales (Nl. Blunted affect; N2. Emotional withdrawal; N3. Poor rapport; N4. Passive/apathetic social withdrawal; N6. Lack of spontaneity; G7. Motor retardation; and G16. Active social avoidance). If a patient has a PANSS assessment recorded, but any of the items are missing, the last non-missing score for the individual item from previous assessments will be carried forward. If more than 30% of the items are missing at a particular visit, the respective positive score is not calculated. It is treated as missing data in the analysis.
- the Positive and Negative Syndrome Scale (PANSS) total score for the subject decreases by at least 10 points than the placebo, for example, after five treatment weeks.
- the PANSS positive subscore decreases by at least 3 points than the placebo, for example, after five treatment weeks.
- the PANSS negative subscore decreases by at least 2 points than the placebo, for example, after five treatment weeks.
- CGI-S Clinical Global Impression - Severity scale
- This 7-point scale requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's experience with patients who have the same diagnosis. Possible ratings are (1) Normal, not at all ill; (2) Borderline mentally ill; (3) Mildly ill, (4) Moderately ill; (5) Markedly ill; (6) Severely ill, and (7) Among the most extremely ill patients.
- CGI-S Clinical Global Impression - Severity scale
- patients Before administering the disclosed combinations, patients may have a lead-in period from one to fourteen days, during which lead-in period trospium chloride is given alone.
- the trospium chloride is administered for one or more dose periods before administering xanomeline to accumulate trospium chloride in the body or for the trospium chloride to reach or approach steady-state exposure levels. This accumulation, or higher exposure levels of the trospium chloride, increases the blockade of muscarinic receptors outside of the brain and reduces adverse events when xanomeline is administered.
- the trospium chloride is administered for one or more days before xanomeline.
- patients may discontinue any prior use of antipsychotic drugs. In some embodiments, the patients will discontinue such drugs for at least one week, such as two weeks. In some embodiments, patients do not discontinue any prior use of such antipsychotic drugs, and the disclosed combinations are co- administered with such drugs.
- xanomeline and trospium chloride are administered to a patient 6 times during a 24-hour period. In another embodiment, xanomeline and trospium chloride are administered to a patient 5 times during a 24-hour period. In another embodiment, xanomeline and trospium chloride are administered to a patient 4 times during a 24-hour period. In an embodiment, xanomeline and trospium chloride are administered to a patient 3 times during a 24-hour period. In another embodiment, xanomeline and trospium chloride are administered to a patient twice during a 24-hour period. In another embodiment, xanomeline and trospium chloride are administered to a patient once during a 24-hour period.
- an extended-release formulation of trospium chloride is used in combination with xanomeline.
- trospium chloride extended-release is administered to a patient from one time to five times during a 24-hour period.
- the extended release of trospium chloride is administered from one to three times during a 24-hour period.
- from five milligrams to 400 milligrams of trospium chloride extended-release is used during a 24-hour period.
- from 20 milligrams to 200 milligrams of trospium chloride extended-release is used during a 24-hour period.
- 225 mg xanomeline and 40 mg trospium chloride are administered to a patient in a 24-hour period.
- 100 mg xanomeline and 20 mg trospium chloride are administered to a patient in a 24-hour period.
- 125 mg xanomeline and 20 mg trospium chloride are administered to a patient in a 24-hour period.
- 125 mg xanomeline and 30 mg trospium chloride are administered to a patient in a 24-hour period.
- 125 mg xanomeline and 40 mg trospium chloride are administered to a patient in a 24-hour period.
- 200 mg xanomeline and 40 mg trospium chloride are administered to a patient in a 24-hour period.
- 200 mg xanomeline and 80 mg trospium chloride are administered to a patient in a 24-hour period.
- 250 mg xanomeline and 60 mg trospium chloride are administered to a patient in a 24-hour period.
- 250 mg xanomeline and 80 mg trospium chloride are administered to a patient in a 24-hour period.
- 300 mg xanomeline and 40 mg trospium chloride are administered to a patient in a 24-hour period.
- 300 mg xanomeline and 60 mg trospium chloride are administered to a patient in a 24-hour period.
- 300 mg xanomeline and 80 mg trospium chloride are administered to a patient in a 24-hour period.
- 350 mg xanomeline and 40 mg trospium chloride are administered to a patient in a 24-hour period.
- 350 mg xanomeline and 60 mg trospium chloride are administered to a patient in a 24-hour period.
- 350 mg xanomeline and 80 mg trospium chloride are administered to a patient in a 24-hour period.
- Treatment may be initiated with smaller dosages. After that, small increments may increase the dosage until a balance between therapeutic effect and side effects is attained.
- the patient's health may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period. Treatment, including composition, amounts, administration, and formulation times, may be adjusted per such monitoring. The patient may be periodically reevaluated to determine improvement by measuring the same parameters. Adjustments to the disclosed composition administered and possibly to the administration time may be made based on these reevaluations.
- a method of treating schizophrenia or a disease related to schizophrenia in a patient in need thereof comprising: orally administering to the patient twice daily an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof, and a plurality of trospium beads comprising a salt of trospium, via a titration scheme that comprises up-titration of the xanomeline, or a salt thereof, and the salt of trospium.
- the xanomeline, or a salt thereof is administered for the first period in a first amount, and then the first amount is increased to a second amount.
- the first amount of xanomeline is equivalent to 50 mg xanomeline free base.
- the first period for the xanomeline administration is between 1 and 5 days, such as 2 days.
- the second amount of xanomeline is equivalent to 100 mg xanomeline free base.
- the method further comprises administering the xanomeline, or a salt thereof, for the second period in the second amount and then increasing the second amount to a third amount.
- the second period for xanomeline administration is between three days and a week.
- the third amount of xanomeline is equivalent to 125 mg xanomeline free base.
- the salt of trospium is administered for the first period in a first amount, and the first amount is increased to a second amount.
- the first amount of the salt of trospium is equivalent to 20 mg trospium chloride.
- the first period for trospium administration is at least a week.
- the second amount of the salt of trospium is equivalent to 30 mg trospium chloride.
- the amount of xanomeline, or a salt thereof, and the salt of trospium administered to the patient is decreased.
- the xanomeline, or a salt thereof, and the salt of trospium are administered without causing a severe adverse event.
- Blood pressure refers to the pressure of circulating blood on the walls of blood vessels. Most of this pressure is due to the heart pumping blood through the circulatory system. Used without further specification, “blood pressure” usually refers to the pressure in large arteries of the systemic circulation. Blood pressure is usually expressed in terms of the systolic pressure (maximum during one heartbeat) over diastolic pressure (minimum in between two heartbeats) and is measured in millimeters of mercury (mmHg), above the surrounding atmospheric pressure.
- Normal resting blood pressure in an adult is about 120 mmHg (16 kPa) systolic and 80 mmHg (11 kPa) diastolic, abbreviated “120/80 mmHg.”
- An adverse event related to blood pressure involves untoward medical occurrence affecting the systolic or diastolic blood pressure or changes to systolic or diastolic blood pressure, including hypertension, hypotension, and syncope (fainting).
- the xanomeline, or a salt thereof, and the salt of trospium are administered without inducing a change in diastolic blood pressure of more than about 5 mmHg.
- the xanomeline, or a salt thereof, and the salt of trospium are administered without inducing a change in systolic blood pressure of more than about 5 mmHg. In certain embodiments, the xanomeline, or a salt thereof, and the salt of trospium are administered without causing a severe adverse event related to blood pressure. In certain embodiments, the xanomeline, or a salt thereof, and the salt of trospium are administered without causing a severe adverse event related to blood pressure change.
- Heart rate refers to the speed of the heartbeat measured by the number of contractions (beats) of the heart per minute (bpm). It is usually equal or close to the pulse measured at any peripheral point.
- the American Heart Association states that the normal resting adult human heart rate is 60-100 bpm.
- Tachycardia is a fast heart rate, defined as above 100 bpm at rest.
- Bradycardia is a slow heart rate, defined as below 60 bpm at rest, except during sleep, when a slow heartbeat with rates around 40-50 bpm is common and normal. When the heart is not beating in a regular pattern, this is referred to as an arrhythmia.
- An adverse event related to heart rate involves an untoward medical occurrence, including tachycardia, bradycardia, and arrhythmia.
- the xanomeline, or a salt thereof, and the salt of trospium are administered without causing a severe adverse event related to heart rate.
- the xanomeline, or a salt thereof, and the salt of trospium are administered without causing a severe adverse event related to heart rate change.
- Liver function tests also referred to as a hepatic panel
- LFTs or LFs are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), aPTT, albumin, bilirubin (direct and indirect), liver transaminases aspartate transaminase (AST or SGOT), alanine transaminase (ALT or SGPT), and others.
- PT/INR prothrombin time
- aPTT albumin
- bilirubin direct and indirect
- liver transaminases aspartate transaminase AST or SGOT
- ALT or SGPT alanine transaminase
- a patient's blood sample is tested for functionality (e.g., albumin), integrity (e.g., transaminase), and conditions linked to the biliary tract (gamma-glutamyl transferase and alkaline phosphata
- the xanomeline, or a salt thereof, and the salt of trospium are administered without increasing a liver function test (LFT).
- LFT liver function test
- the xanomeline, or a salt thereof, and the salt of trospium are administered without causing elevated LFT.
- the liver function test is chosen from prothrombin time (PT/INR), aPTT, albumin, bilirubin (direct and indirect), liver transaminases aspartate transaminase (AST or SGOT), and alanine transaminase (ALT or SGPT).
- the xanomeline, or a salt thereof, and the salt of trospium are administered without increasing at least one of ALT, AST, Aik phos, or bilirubin. In some embodiments, the xanomeline, or a salt thereof, and the salt of trospium are administered without increasing ALT, AST, Aik phos, or bilirubin.
- the present disclosure further provides a method of treating acute psychosis in a patient in need thereof.
- the method comprises orally administering to the patient twice daily an oral pharmaceutical composition comprising xanomeline or a salt thereof, and a salt of trospium.
- At least about an 11.6 point mean reduction in total PANNS score is achieved.
- at least a 3 point mean reduction in PANSS positive subscore compared to placebo is achieved.
- at least a 2 point reduction in the PANSS negative subscore compared to placebo is achieved.
- the reduction in the PANSS score is achieved within about 5 weeks.
- the patient before administering the oral pharmaceutical composition, the patient had a Clinical Global Impression Severity Scale (CGI-S) score of 4-7.
- CGI-S Clinical Global Impression Severity Scale
- the patient has a diagnosis of schizophrenia. In certain embodiments, the patient has acute psychosis. In certain embodiments, the patient has psychosis associated with Alzheimer’s disease. In certain embodiments, the patient has a schizo-affective disorder. In certain embodiments, the patient has psychosis. In certain embodiments, the patient has a delusional disorder. In certain embodiments, the patient has psychosis associated with Parkinson’s disease. In certain embodiments, the patient has psychotic depression. In certain embodiments, the patient has bipolar disorder. In certain embodiments, the patient has bipolar disorder with psychosis. In certain embodiments, the patient has Huntington’s disease. In certain embodiments, the patient has Lewy Body dementia.
- the patient previously had been administered one or more antipsychotics.
- the patient was an inadequate responder to such administration ⁇
- the patient was treatment-resistant.
- the patient is an adult. In certain embodiments, the patient is elderly, e.g., above the age of 65 years. In certain embodiments, the patient has dementia- related psychosis.
- the powders were screened using Quadro Comil Model 197 equipped with 457- ⁇ m round hole screen, 0.2-inch spacer at 1625 rpm and mixed for 2 min in a Hobart low shear mixer/granulator (model N-50) at a fixed speed of 60 rpm.
- the dry blending step is optional, as blend uniformity is driven by subsequent wet granulation. Beads were screened by hand through a 40 mesh (425 ⁇ m) sieve.
- the extrudates were placed into an LCI Marumerizer (spheronizer) QJ-230T equipped with a 2.0 mm friction plate.
- the extrudates were spheronized at different plate speeds for a total of not more than 4 minutes. Spheronization speed and time are process variables.
- the beads were dried using an AeromaticTM Strea- 1 fluid bed at an inlet temperature of 60 °C until a water content of not more than 3% was obtained. Because beads melted after a few minutes at 60 °C, the beads were dried at 30 °C.
- Ph. Eur European Pharmacopeia
- USP United States Pharmacopeia * - Evaporated during the process thus not included in total weight
- An oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof, and a plurality of trospium beads comprising a salt of trospium is referred to as “KarXT.”
- KarXT may be formulated in many dosage strengths, for example, as exemplified below KarXT 50/10, KarXT 50/20, and KarXT 75/20, wherein the number before the slash is the milligrams of xanomeline free base in the composition (X) and the number after the slash is the milligrams of trospium chloride in the composition (T).
- Capsules were produced by weighing beads and filling into HPMC capsules manually. Beads were encapsulated by hand using an AccofilTM capsule filling machine where beads premixed with talc (0.5%) were filled individually /one-after-the-other in the capsule, as shown in Table 19.
- Table 9 Composition of Xanomeline / Trospium Chloride Capsules. Ingredients are listed in milligrams per capsule.
- the beads were screened by shaking 5 min through 16 mesh (1.18 mm) and 40 mesh (0.425 mm) screens. The beads in size between sieves 1.18 mm and 0.425 mm were retained for further analysis.
- the morphology and surface characteristics of beads were examined by scanning electron microscopy (SEM) using a JSM-6010LV InTouchScopeTM (JEOL Ltd, Tokyo, JP) microscope with a back-scattered electron detector (BES). Samples were placed on metallic stubs using double-sided carbon conductive tape. The images were obtained with accelerating voltages of 20 kV under low vacuum (60 Pa) and magnification 30x.
- the beads were further sized between 0.6 mm and 0.85 mm. Some beads exhibited similar morphological properties. Modifications in some other beads decreased the density of beads and led to rough surfaces and sphericity loss. Scanning electron microscope (SEM) images of xanomeline tartrate 66% beads and trospium chloride 17.7% beads at 30x magnification showed that the beads are sized between 0.6 mm and 0.85 mm. These beads were used in xanomeline/trospium capsules. Particle size distribution (PSD) of beads was determined by mechanical sieving. As shown in Table 10, most beads for both APIs were sized between 0.425 and 1.18 mm.
- SEM scanning electron microscope
- Table 10 Particle Size Distribution by Mechanical Sieving of Beads [0287]
- Table 11 shows the densities and flow properties of beads collected between 0.425 mm and 1.18 mm sieves. Xanomeline tartrate and trospium chloride IR beads showed different densities and flow properties, which can be critical when mixing bead systems.
- Table 12 shows favorable results for assay and related substances and moisture content for 50 mg xanomeline and 20 mg trospium chloride capsules. Data in Table 13 show that these attributes were retained during storage stability studies. Similar data are provided for the 50 mg xanomeline and 10 mg trospium chloride capsules in Table 14. Dissolution data for these two dosage forms are provided in Table 15 and Table 16.
- Table 16 Dissolution of KarXT 50/10 were stable for at least 12 months 25°C/60%RH. Based on available data, a shelf-life of 15 months at 25°C/60%RH is proposed.
- the storage temperature for the drug product was lowered. Bottles were flushed with argon to minimize headspace oxygen during packaging.
- the xanomeline bead formulation was formulated with an antioxidant, such as 0.5 wt.% ascorbic acid or 0.05 wt.% BHT.
- a Phase I, double-blind, randomized multiple-dose pilot study was conducted with xanomeline administered alone compared to xanomeline administered with trospium chloride in normal healthy volunteers.
- the primary objectives of this study were (1) to assess the safety and tolerability of administering, for 7 days, 225 mg daily of xanomeline with 40 mg daily of trospium chloride, versus administering 225 mg daily of xanomeline alone for 7 days; and (2) to determine whether adding trospium 40 mg daily (20 mg BID) to xanomeline 225 mg daily (75 mg TID) over 7 days significantly reduces peripheral cholinergic side effects (nausea, diarrhea, vomiting, sweating, excess salivation) versus xanomeline 225 mg daily, alone.
- Table 17 lists the parameters from this study.
- each kind of individual cholinergic adverse event also had a decreased incidence rate in subjects administered xanomeline + trospium chloride, compared to the incidence rate in subjects administered xanomeline + placebo.
- Table 19 shows the incidence and number of cholinergic adverse events in the evaluable population of the study were as follows, with all p- values based on a chi-squared test, except those marked with an *, which were based on a Fisher’s exact test.
- This study was a Phase 1 , randomized, multiple-dose, adaptive design, inpatient study to assess the safety and tolerability of KarXT in normal healthy volunteers aged 18 to 60 years. Subjects signed the informed consent and underwent Screening assessments on Days -21 to -1. Upon completing all Screening assessments, subjects returned to the study clinic on Day 0 for baseline safety assessments and enrollment into the study. They were randomized 3: 1 in each cohort into one of two treatment arms: KarXT or placebo. Subjects were assigned to 1 of 4 cohorts (Cohort 1, 2, 3, or 4).
- Study drug was administered BID on Days 1 through 7.
- a combination dosage formulation of both xanomeline and trospium was used in all cohorts. All cohorts began with a 2-day lead-in of KarXT 50/20 BID (for subjects randomized to active treatment); after the 2-day lead-in period, the unblinded pharmacist dispensed the study drug to each subject per the subject’s randomization assignment for 5 days of specified cohort dosing, for a total of 7 days of treatment. A matching placebo was administered throughout the study to maintain the blind.
- a sentinel group was introduced to the study for Cohorts 2 to 4. It was monitored for safety and tolerability by the Data Safety Evaluation Group (DSEG), such that about 30% of the proposed cohort was treated and assessed for safety before the rest of the cohort was dosed. Subjects and study clinic staff were blinded to treatment. The Dose Selection Committee (DSC) was unblinded to decide to dose for subsequent treatment groups.
- DSEG Data Safety Evaluation Group
- the second group in Cohort 3 (Group 3b) discontinued dosing after the Day 5 morning dose.
- Table 21 Summary of Demographics and Baseline Characteristics by Treatment Group - Safety Population
- Safety evaluations included spontaneously reported adverse events, ECGs, laboratory assessments, vital signs, assessments of saliva volumes, Bristol stool scale, pupil size, and physical examinations ⁇ Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) summarized the treatment group's continuous data. Geometric mean (GM), geometric percent coefficient of variation (CV%), quartiles, or box plots was generated. The count and frequency tabulated categorical measurements, although formal statistics were not conducted.
- Treatment groups were summarized as follows unless otherwise specified: KarXT 50/20 BID (for adverse events and Day 1 PK summaries only), KarXT 100/20 BID, KarXT 125/40 BID, KarXT 150/20 BID, KarXT 150/40 BID, and placebo (Empty Vcaps ® Plus Capsules and Capsugel ® ; all cohort placebo groups combined).
- the safety evaluation was based on reported adverse events, ECGs, laboratory assessments, and vital signs. Exploratory analyses of saliva volumes, Bristol stool scale, and pupil size were also conducted.
- Xanomeline was well absorbed into the systemic circulation following oral administration of the KAR-003 formulation at all dosages. Peak concentrations of xanomeline were observed at a median time of 2 hours across all treatment groups and study days.
- GM xanomeline exposures did not increase dose-proportionally on Day 3 from 100 to 150 mg when xanomeline was administered with 20 mg trospium or 125 to 150 mg when administered with 40 mg trospium. Lower xanomeline exposures were observed following treatment with KarXT 150/40 compared to KarXT 125/40.
- Day 3 GM xanomeline exposures (C max , AUC 0-last , and AUC 0-12hr ) were similar when the 150 mg xanomeline dose was administered with 20 and 40 mg trospium.
- GM xanomeline exposures increased slightly more than dose-proportionally from 125 to 150 mg when xanomeline was administered 40 mg trospium.
- Example 6 Xanomeline pharmacokinetics of KAR-003 compared to KAR-001
- Comparing xanomeline GM exposures between KAR-001 (75 mg xanomeline TID ⁇ 20 mg trospium BID) and the KarXT 100/20 BID group from KAR-003 showed that C max values and AUC 0-6hr (KAR-003) or AUC 0-tau (KAR-001) values were greater in KAR-003 (Days 3 and 7) than the corresponding exposures from KAR-001 (Days 3 and 9).
- the median T max was observed at 2 hours in both studies and both days (Days 3 and 9 for KAR-001, and Days 3 and 7 for KAR-003).
- Trospium was absorbed into the systemic circulation following oral administration of the KarXT formulation at all dosages. Peak concentrations of trospium were observed at a median time of 1.0 hour across all treatment groups and study days.
- GM trospium exposures increased slightly less than dose-proportionally on Day 3 from 20 to 40 mg when administered with 150 mg xanomeline.
- Day 3 GM trospium exposures (C max , AUC 0-last , and AUC 0-12hr ) were greater when the 20 mg BID dose of trospium was administered with 100 mg BID xanomeline compared to 150 mg BID xanomeline.
- Day 3 GM trospium exposures were similar when the 40 mg trospium BID dose was given 125 mg xanomeline BID and 150 mg xanomeline BID.
- Trospium did not accumulate in plasma from Day 3 to Day 7 following administration of KarXT 100/20 BID, KarXT 125/40 BID, and KarXT 150/40 BID. Trospium accumulated in plasma from Day 1 to Day 7 for the KarXT 100/20 BID group. Mean Day 7/Day 1 accumulation ratios were 348.7% (RAUC) and 379.9% (RC max ).
- FIG. 1 presents the mean ( ⁇ SD) xanomeline PK concentrations
- Table 22 summarizes xanomeline PK parameters on Day 1 for KarXT 50/20 BID treatment of all cohorts for the PK Population. No sample collected before administering the first dose of xanomeline on Day 1 displayed measurable concentrations of xanomeline. Concentrations of xanomeline were quantifiable (>50 pg/mL) at all time points after administering the Day 1 morning dose through 12 hours.
- Table 22 Xanomeline PK Parameters on Day 1 for KarXT 50/20 BID (All Cohorts)
- FIG. 2 presents the mean ( ⁇ SD) xanomeline PK concentrations by treatment on Day 3 for the PK population, and Table 23 summarizes these parameters. Concentrations of xanomeline were quantifiable in samples before administering the morning dose of the study drug on Day 3 and at all time points after administering the Day 3 morning dose through 12 hours for all cohorts, except for one subject who had a xanomeline plasma concentration ⁇ 50.0 pg/mL at 12 hours post-dose.
- the Day 3 dose-normalized GM exposures for xanomeline decreased slightly (i.e., xanomeline exposures were lower following treatment with KarXT 150/40 BID compared to treatment with KarXT 125/40 BID). Comparing xanomeline exposures following 150 mg xanomeline BID administration with either 20 or 40 mg trospium BID showed that the Day 3 GM, C max , AUC 0-last , and AUC 0-12hr for xanomeline were similar.
- FIG. 3 presents the mean ( ⁇ SD) xanomeline PK concentrations by treatment on Day 7 for the PK population, and Table 24 summarizes these parameters. Concentrations of xanomeline were quantifiable in samples collected before administering the morning dose of the study drug on Day 7 and at all time points after the Day 7-moming dose through 12 hours for the KarXT 100/20 BID, KarXT 125/40 BID, and KarXT 150/40 BID groups.
- KarXT 125/40 BID, and KarXT 150/40 BID groups are KarXT 125/40 BID, and KarXT 150/40 BID groups. Individual T max values ranged from 0.0 to 6.0 hours across the KarXT 100/20 BID, KarXT 150/40 BID, and KarXT 125/40 BID groups. The median t 1/2 for xanomeline on Day 7 was numerically similar for the KarXT 100/20 BID, KarXT 125/40 BID, and KarXT 150/40 BID groups. Median t 1/2 for xanomeline ranged from 4.6 to 5.8 hours. Individual tm values ranged from 3.6 to 14.0 hours across the KarXT 100/20 BID, KarXT 150/40 BID, and KarXT 125/40 BID groups.
- Table 25 summaries xanomeline PK accumulation ratios (Day 7/Day 3) by treatment for the PK population. Based upon mean accumulation ratios of xanomeline following treatment with KarXT 100/20 BID (Cohort 1) and KarXT 125/40 BID (Cohort 4), minimal to no xanomeline accumulated in plasma from Day 3 to Day 7.
- the KarXT 100/20 BID group's mean accumulation ratios were 133.4% for RAUC and 130.5% for RC max , and for the KarXT 125/40 BID group was 143.9% for RAUC and 151.0% for RC max . Only one subject in the KarXT 100/20 BID group showed lower exposures on Day 7 compared to Day 3.
- xanomeline accumulated moderately in three of the four subjects in the KarXT 150/40 BID group who completed the study.
- the other subject in the KarXT 150/40 BID group showed similar exposures on Days 3 and 7.
- the KarXT 150/40 BID group's mean accumulation ratios were 366.2% (RAUC) and 445.4% (RC max ).
- Table 25 Xanomeline PK Accumulation Ratios (Day 7/Day 3) by Treatment
- FIG. 4 compares the mean ( ⁇ SD) xanomeline PK concentration-time profiles by treatment and visit (Day) for the PK population.
- FIG. 5 presents mean ( ⁇ SD) xanomeline PK trough concentrations by treatment for the PK population. Attaining a steady-state was not assessed.
- Table 26 summarizes a subset of KAR-003 xanomeline PK parameters for the KarXT 100/20 BID group on Day 3 and Day 7 for the PK Population.
- Table 27 presents a summary of a subset of KAR-001 xanomeline PK parameters for the treatments of KAR-001 on Day 3 and Day 9 for the PK Population.
- FIG. 6 presents mean ( ⁇ SD) trospium PK concentrations on Day 1 for the KarXT 50/20 BID treatment (all cohorts) for the PK population, and Table 28 summarizes these parameters. No samples collected before administering the first dose of trospium on Day 1 displayed measurable concentrations of trospium. Concentrations of trospium were quantifiable (>20 pg/mL) at all time points after administration of the Day 1 morning dose through 12 hours.
- FIG. 7 presents mean ( ⁇ SD) trospium PK concentrations by treatment on Day 3 for the PK population, and Table 29 summarizes these parameters. Concentrations of trospium were quantifiable in samples collected before administering the morning dose of the study drug on Day 3 and at all time points after administering the Day 3 morning dose through 12 hours for all treatment groups (except for one subject who had a trospium plasma concentration ⁇ 20.0 pg/mL at 12 hours post-dose.
- Inter-subject variability ranged from 0.0% to 83.0% (CV%) for T max , 54.8% to 80.7% (geometric CV%) for C max , 9.1% to 34.0% (CV%) for t 1/2 , and 59.0% to 67.6 % (geometric CV%) for AUC 0-12hr across the four treatment groups.
- the median T max for trospium on Day 3 was 1.0 hour for the KarXT 100/20 BID, KarXT 125/40 BID, KarXT 150/20 BID, and KarXT 150/40 BID groups. Individual T max values ranged from 1.0 to 6.0 hours across the 4 treatment groups.
- the median t 1/2 for trospium on Day 3 was numerically similar across the 4 treatment groups; median t 1/2 ranged from 4.1 to 4.8 hours. Individual t 1/2 values ranged from 2.8 to 9.0 hours across the 4 treatment groups.
- FIG. 8 presents mean ( ⁇ SD) trospium PK concentrations by treatment on Day 7 for the PK population, and Table 30 summarizes the parameters. Concentrations of trospium were quantifiable in samples collected before administering the morning dose of the study drug on Day 7 and at all time points after the Day 7 morning dose through 12 hours for the KarXT 100/20 BID, KarXT 125/40 BID, and KarXT 150/40 BID groups.
- Inter-subject variability ranged from 0.0% to 86.3% (CV%) for T max , 51.2% to 93.8% (geometric CV%) for Cmax, 23.0% to 44.5% (CV%) for ti/2, and 59.4% to 76.7% (geometric CV%) for AUC 0-12hr across the KarXT 100/20 BID, KarXT 150/40 BID, and KarXT 125/40 BID groups.
- the median T max for trospium on Day 7 was 1.0 hour for the KarXT 100/20 BID, KarXT 125/40 BID, and KarXT 150/40 BID treatments. Individual T max values ranged from 0.0 to 6.0 hours across the KarXT 100/20 BID, KarXT 150/40 BID, and KarXT 125/40 BID groups.
- the median t 1/2 for trospium on Day 7 was similar for the KarXT 100/20 BID (4.9 hours) and KarXT 125/40 BID (4.5 hours) groups.
- the median t 1/2 was 7.1 hours for the KarXT 150/40 BID group.
- Individual t 1/2 values ranged from 3.1 to 11.9 hours across the KarXT 100/20 BID, KarXT 150/40 BID, and KarXT 125/40 BID groups.
- Table 31 summarizes trospium PK accumulation ratios (Day 7/Day 3; Day 7/Day 1) by treatment for the PK Population. Based upon mean trospium PK accumulation ratios, trospium accumulated minimally in the plasma from Day 3 to Day 7 following administration of KarXT 100/20 BID (Cohort 1) and had little to no accumulation following administration of KarXT 125/40 BID (Cohort 4) and KarXT 150/40 BID (Cohort 3). Two subjects showed lower exposures on Day 7 compared to Day 3 in the KarXT 100/20 BID group.
- FIG. 9 compares mean ( ⁇ SD) trospium PK concentration-time profiles by treatment and visit (Day) for the PK Population.
- FIG. 10 presents mean ( ⁇ SD) trospium PK trough concentrations by treatment and visit (Day) for the PK Population. Attaining a steady state was not assessed.
- Example 7 Trospium pharmacokinetics of KAR-003 compared to KAR-001 [0344] Comparing GM exposures for trospium from Day 1 of KAR-001 (first dose of trospium alone with no prior treatment) (Table 33) and Day 1 of KAR-003 (first dose of xanomeline + trospium with no prior treatment) (Table 32) shows that the trospium exposures from KAR-003 are about 2.1- to 2.5-fold higher than those obtained from KAR-001.
- the median T max for trospium was 1.0 hour on Day 3 and Day 7 for the KarXT 100/20 BID group for KAR-003 and Day 3 and Day 9 for the xanomeline + trospium arm for KAR- 001.
- Median T max for trospium was lower (1.0 hour) on Day 1 for the KarXT 50/20 BID group (KAR-003) compared to the median T max for trospium (3.0 hours on Day 1 for the trospium alone arm (KAR-001).
- Table 32 summarizes a subset of KAR-003 trospium PK parameters for the KarXT 50/20 BID treatment (all cohorts) on Day 1 and the KarXT 100/20 BID treatment Day 3 and Day 7 for the PK Population.
- Table 33 summarizes a subset of KAR-001 trospium PK parameters for the trospium-alone treatment on Day 1 and the xanomeline + trospium treatment on Day 3 and Day 9 for the PK Population.
- Table 32 Subset of KAR-003 Trospium PK Parameters for KarXT 50/20 BID (All Cohorts) on Day 1 and KarXT 100/20 BID on Days 3 and 7
- Table 34 lists the incidence of cholinergic TEAEs by system organ class (SOC) and preferred term for the Safety Population in the KAR-001 study.
- SOC system organ class
- the overall subject incidence of cholinergic TEAEs was similar between the xanomeline + trospium arm (12 [34.3%] subjects) in KAR-001, the KarXT 100/20 BID group (7 [38.9%] subjects), and the KarXT 125/40 BID group (6 [33.3%] subjects).
- Salivary hypersecretion occurred in 25.7 % of subjects in the xanomeline + trospium arm in KAR-001, 5.6% of subjects in the KarXT 100/20 BID group, and no subjects in the KarXT 125/40 BID group.
- Hyperhidrosis occurred in 20.0% of subjects in the xanomeline + trospium arm in KAR-001, 5.6% of subjects in the KarXT 100/20 BID group, and 11.1% of subjects in the KarXT 125/40 BID group.
- Diarrhea occurred in 5.7% of subjects in the xanomeline + trospium arm in KAR-001, and no subjects in the KarXT 100/20 BID group or the KarXT 125/40 BID group.
- the xanomeline + trospium arm in KAR-001 showed no other apparent trends than the KarXT 100/20 BID and KarXT 125/40 BID groups for nausea and vomiting. Nausea occurred in 17.1% of subjects in the xanomeline + trospium arm in KAR-001 and 22.2% of subjects in each KarXT 100/20 BID and KarXT 125/40 BID groups. Vomiting occurred in 5.7% of subjects in the xanomeline + trospium arm in KAR-001, 27.8% of subjects in the KarXT 100/20 BID group, and 5.6% of subjects in the KarXT 125/40 BID group.
- Xanomeline and trospium were absorbed into the systemic circulation following oral administration of the KAR-003 formulation at all dosages.
- the PK results suggest that neither xanomeline nor trospium meaningfully impacted the PK behavior of the other drug.
- the KAR-003 formulation provided enhanced xanomeline and trospium blood levels compared to KAR-001, where both compounds were dosed apart.
- This Phase II, randomized, double-blind, placebo-controlled, inpatient study was designed to assess the efficacy of KarXT (a fixed combination of xanomeline and trospium) versus placebo in reducing Positive and Negative Syndrome Scale (PANSS) total scores in adult inpatients with a diagnosis of schizophrenia.
- the five secondary objectives were to assess overall safety and tolerability of KarXT in adult inpatients with a DSM-5 diagnosis of schizophrenia, to assess spontaneously reported adverse events (AEs) in subjects treated with KarXT versus placebo, to assess spontaneously reported cholinergic symptoms in subjects treated with KarXT versus placebo, to assess orthostatic vital signs in subjects treated with KarXT versus placebo, and to assess ECG parameters in subjects treated with KarXT versus placebo.
- AEs spontaneously reported adverse events
- the total study duration was up to 7 weeks, including a 7-day screening phase (up to a 7-day extension of the screening phase was allowed, if necessary), and a 5-week treatment period.
- Subjects were randomized in a 1:1 ratio to either KarXT or placebo group.
- the key inclusion and exclusion criteria for the Phase II study are shown in Table 35.
- the demographics and baseline characteristics of the enrolled patients are shown in Table 36.
- Table 36 Demographics and Baseline Characteristics of the Enrolled Patients
- the primary endpoint was a change in total PANSS score from baseline versus placebo at week 5.
- the other endpoints included CGI, PANSS-positive and -negative subscales, PANSS Marder factor, cognitive battery, and others.
- a CGI-S responder is defined as a subject with a CGI-S score equal to 1 or 2.
- a CGI-S non-responder is defined as a subject with a CGI-S scale equal to 3 to 7. The subject required a CGI-S score of ⁇ 4 at screening and baseline visits.
- CGI-S score legend rated 1 as normal, 2 as borderline ill, 3 as mildly ill, 4 as moderately ill, 5 as markedly ill, 6 as severely ill, and 7 as extremely ill.
- the safety endpoints comprised monitoring for spontaneous adverse events, orthostatic vital signs (supine and standing after 2 minutes), blood pressure (systolic and diastolic) and heart rate (beats/minute), clinical laboratory evaluations (hematology, clinical chemistry, coagulation, urinalysis, and drug screen), 12-lead ECG, physical examination, and rating suicidal ideation with the Columbia Suicide Severity Rating Scale (C-SSRS).
- C-SSRS Columbia Suicide Severity Rating Scale
- the Intent-to-Treat (ITT) population comprised all subjects who were randomized to the study.
- the Safety population comprised all subjects who received at least one dose of study medication.
- the Safety population was used for all analyses of safety endpoints.
- the modified Intent-to-Treat (mITT) population comprised all subjects who were randomized, received at least one dose of study medication, and had a baseline and at least one post- baseline PANSS assessment.
- the mITT population was used for all analyses of efficacy endpoints.
- the PK population comprised all subjects who received at least one dose of the study drug and had at least one measurable PK concentration.
- the Completer population comprised all mITT subjects who had a valid PANSS total score at Visit 9.
- the Completer population was used for sensitivity analysis of the primary efficacy endpoint.
- Per- Protocol (PP) population comprised all subjects who were randomized, received at least one dose of study medication, had a baseline and at least one post-baseline PANSS assessment, and had no major protocol deviations.
- the PP population was used for sensitivity analysis of the primary efficacy endpoint. All subjects were analyzed according to randomized treatment.
- the KarXT treatment group demonstrated clinically meaningful and statistically significant improvement in total PANSS-positive subscore versus placebo (FIG. 12). The subjects improved by 3.2 points compared to placebo at week 5 (p ⁇ 0.0001). Statistical separation occurred at every assessment timepoint.
- the KarXT treatment group also demonstrated a clinically meaningful and statistically significant improvement in total PANS S -negative versus placebo (FIG. 13). The subjects improved by 2.3 points compared to placebo at week 5 (p ⁇ 0.001). Statistical separation occurred at every assessment timepoint.
- FIG. 14 depicts the PANSS Marder Factor score of subjects in the mITT population of KAR-004 Phase II study versus Visit day.
- CGI-S showed highly significant improvements in a consistent pattern with the PANSS.
- the non-parametric comparison of KarXT versus placebo using the Mann- Whitney Wilcoxon test showed that CGI-S scores shifted from baseline (p ⁇ 0.001).
- the percentage of patients with scores 5 or 6 for KarXT compared to placebo 84% vs. 80% (FIG. 15).
- the percentage of patients with scores rated 5-7 for KarXT compared to placebo was 33% versus 60%, and the percentage of patients rated mildly ill or better (scores rated 1, 2, or 3) for KarXT compared to placebo were 37% versus 11% (FIG. 16).
- Statistical separation occurred at every assessment time point (weeks 2, 4, and 5).
- liver enzymes in the LFT were comparable to placebo (Table 39).
- Two KarXT- treated patients had elevated GGT (> 2X ULN) and one placebo-treated patient with elevated ALT (> 3X ULN), AST (> 3X ULN), and GGT (> 2X ULN).
- GGT gamma-glutamyltransferase
- ALT alanine aminotransferase
- AST aspartate aminotransferase
- Aik phos alkaline phosphatase
- GGT gamma- glutamyltransferase.
- compositions are described as including components or materials, it is contemplated that the compositions can also consist essentially of, or consist of, any combination of the recited components or materials, unless described otherwise.
- methods are described as including steps, it is contemplated that the methods can also consist essentially of, or consist of, any combination of the recited steps, unless described otherwise.
- the disclosure illustratively disclosed herein suitably may be practiced in the absence of any element or step which is not specifically disclosed herein.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP20888871.9A EP4061808A4 (en) | 2019-11-18 | 2020-11-17 | COMPOSITIONS AND METHODS FOR THE TREATMENT OF DISEASES RELIEVED BY ACTIVATION OF THE MUSCARINE RECEPTOR |
CA3161952A CA3161952A1 (en) | 2019-11-18 | 2020-11-17 | Compositions and methods for treating disorders ameliorated by muscarinic receptor activation |
JP2022529029A JP2023503056A (ja) | 2019-11-18 | 2020-11-17 | ムスカリン受容体活性化によって改善される障害を処置するための組成物及び方法 |
CN202080093687.1A CN115667235A (zh) | 2019-11-18 | 2020-11-17 | 用于治疗由毒蕈碱受体激活所缓解的障碍的组合物和方法 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201962936837P | 2019-11-18 | 2019-11-18 | |
US62/936,837 | 2019-11-18 | ||
US202063030780P | 2020-05-27 | 2020-05-27 | |
US63/030,780 | 2020-05-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2021101875A1 true WO2021101875A1 (en) | 2021-05-27 |
Family
ID=75980892
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2020/060859 WO2021101875A1 (en) | 2019-11-18 | 2020-11-17 | Compositions and methods for treating disorders ameliorated by muscarinic receptor activation |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP4061808A4 (zh) |
JP (1) | JP2023503056A (zh) |
CN (1) | CN115667235A (zh) |
CA (1) | CA3161952A1 (zh) |
WO (1) | WO2021101875A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11452692B2 (en) | 2018-09-28 | 2022-09-27 | Karuna Therapeutics, Inc. | Compositions and methods for treating disorders ameliorated by muscarinic receptor activation |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110020423A1 (en) * | 2009-07-22 | 2011-01-27 | Puretech Ventures | Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation |
US20170095465A1 (en) * | 2009-07-22 | 2017-04-06 | PureTech Health LLC | Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation |
US20170313687A1 (en) * | 2010-01-11 | 2017-11-02 | Neurosolis, Inc. | Compounds and Compositions for Cognition-Enhancement, Methods of Making, and Methods of Treating |
US20200289419A1 (en) * | 2018-09-28 | 2020-09-17 | Karuna Therapeutics, Inc. | Compositions and methods for treating disorders ameliorated by muscarinic receptor activation |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8216609B2 (en) * | 2002-08-05 | 2012-07-10 | Torrent Pharmaceuticals Limited | Modified release composition of highly soluble drugs |
-
2020
- 2020-11-17 CA CA3161952A patent/CA3161952A1/en active Pending
- 2020-11-17 WO PCT/US2020/060859 patent/WO2021101875A1/en unknown
- 2020-11-17 CN CN202080093687.1A patent/CN115667235A/zh active Pending
- 2020-11-17 EP EP20888871.9A patent/EP4061808A4/en active Pending
- 2020-11-17 JP JP2022529029A patent/JP2023503056A/ja active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110020423A1 (en) * | 2009-07-22 | 2011-01-27 | Puretech Ventures | Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation |
US20170095465A1 (en) * | 2009-07-22 | 2017-04-06 | PureTech Health LLC | Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation |
US20170313687A1 (en) * | 2010-01-11 | 2017-11-02 | Neurosolis, Inc. | Compounds and Compositions for Cognition-Enhancement, Methods of Making, and Methods of Treating |
US20200289419A1 (en) * | 2018-09-28 | 2020-09-17 | Karuna Therapeutics, Inc. | Compositions and methods for treating disorders ameliorated by muscarinic receptor activation |
Non-Patent Citations (1)
Title |
---|
See also references of EP4061808A4 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11452692B2 (en) | 2018-09-28 | 2022-09-27 | Karuna Therapeutics, Inc. | Compositions and methods for treating disorders ameliorated by muscarinic receptor activation |
US11890378B2 (en) | 2018-09-28 | 2024-02-06 | Karuna Therapeutics, Inc. | Compositions and methods for treating disorders ameliorated by muscarinic receptor activation |
Also Published As
Publication number | Publication date |
---|---|
CN115667235A (zh) | 2023-01-31 |
EP4061808A1 (en) | 2022-09-28 |
CA3161952A1 (en) | 2021-05-27 |
EP4061808A4 (en) | 2023-12-20 |
JP2023503056A (ja) | 2023-01-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
IL289974B (en) | Methods and processes for non-invasive evaluation of genetic variations | |
US11452692B2 (en) | Compositions and methods for treating disorders ameliorated by muscarinic receptor activation | |
US20210145804A1 (en) | Compositions and methods for treating disorders ameliorated by muscarinic receptor activation | |
EA038198B1 (ru) | Способы и композиции, в частности, для лечения синдрома дефицита внимания | |
US20240156802A1 (en) | Methods for treating disorders ameliorated by muscarinic receptor activation | |
EP4061808A1 (en) | Compositions and methods for treating disorders ameliorated by muscarinic receptor activation | |
US20240238205A1 (en) | Compositions and methods for treating disorders ameliorated by muscarinic receptor activation | |
CN117136048A (zh) | 用于治疗由毒蕈碱受体激活所缓解的障碍的方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 20888871 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 3161952 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2022529029 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2020888871 Country of ref document: EP Effective date: 20220620 |