CN112739679A - 曲前列环素的特丁胺盐 - Google Patents
曲前列环素的特丁胺盐 Download PDFInfo
- Publication number
- CN112739679A CN112739679A CN201980060738.8A CN201980060738A CN112739679A CN 112739679 A CN112739679 A CN 112739679A CN 201980060738 A CN201980060738 A CN 201980060738A CN 112739679 A CN112739679 A CN 112739679A
- Authority
- CN
- China
- Prior art keywords
- treprostinil
- tert
- salt
- butylamine
- tetramine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical class CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 title description 19
- 229960005032 treprostinil Drugs 0.000 claims abstract description 56
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical class C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 6
- -1 Treprostinil tert-butylamine salt Chemical class 0.000 claims description 26
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 16
- 238000002441 X-ray diffraction Methods 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 108090001061 Insulin Proteins 0.000 claims description 7
- 102000004877 Insulin Human genes 0.000 claims description 7
- 229940125396 insulin Drugs 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 108010065920 Insulin Lispro Proteins 0.000 claims description 4
- WNRQPCUGRUFHED-DETKDSODSA-N humalog Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 WNRQPCUGRUFHED-DETKDSODSA-N 0.000 claims description 4
- 229960002068 insulin lispro Drugs 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 230000000144 pharmacologic effect Effects 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- AGGKEGLBGGJEBZ-UHFFFAOYSA-N tetramethylenedisulfotetramine Chemical compound C1N(S2(=O)=O)CN3S(=O)(=O)N1CN2C3 AGGKEGLBGGJEBZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012296 anti-solvent Substances 0.000 claims description 2
- 201000001421 hyperglycemia Diseases 0.000 claims description 2
- NTZZEBUPDUXPKO-UHFFFAOYSA-N 2-methylpropan-2-amine Chemical compound CC(C)(C)N.CC(C)(C)N NTZZEBUPDUXPKO-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 12
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000002253 acid Substances 0.000 description 8
- 159000000000 sodium salts Chemical class 0.000 description 7
- 238000002411 thermogravimetry Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 238000001179 sorption measurement Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 229940118867 remodulin Drugs 0.000 description 3
- 238000001757 thermogravimetry curve Methods 0.000 description 3
- IQKAWAUTOKVMLE-ZSESPEEFSA-M treprostinil sodium Chemical class [Na+].C1=CC=C(OCC([O-])=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 IQKAWAUTOKVMLE-ZSESPEEFSA-M 0.000 description 3
- 229940014025 tyvaso Drugs 0.000 description 3
- 108010073961 Insulin Aspart Proteins 0.000 description 2
- RCHHVVGSTHAVPF-ZPHPLDECSA-N apidra Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CNC=N1 RCHHVVGSTHAVPF-ZPHPLDECSA-N 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- 229950005127 erbumine Drugs 0.000 description 2
- 229960004717 insulin aspart Drugs 0.000 description 2
- 108700039926 insulin glulisine Proteins 0.000 description 2
- 229960000696 insulin glulisine Drugs 0.000 description 2
- VOMXSOIBEJBQNF-UTTRGDHVSA-N novorapid Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 VOMXSOIBEJBQNF-UTTRGDHVSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 208000002815 pulmonary hypertension Diseases 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical class CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- CDMVQQAHEQVSMF-AULARHRYSA-N 3-[(3s,5s,8r,9s,10r,13r,14s,17r)-3,14-dihydroxy-10-(hydroxymethyl)-13-methyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]-2h-furan-5-one Chemical compound C1([C@H]2CC[C@]3(O)[C@H]4[C@@H]([C@]5(CC[C@H](O)C[C@@H]5CC4)CO)CC[C@@]32C)=CC(=O)OC1 CDMVQQAHEQVSMF-AULARHRYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 101001011741 Bos taurus Insulin Proteins 0.000 description 1
- 208000008960 Diabetic foot Diseases 0.000 description 1
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- 108010005991 Pork Regular Insulin Proteins 0.000 description 1
- 229940123452 Rapid-acting insulin Drugs 0.000 description 1
- 108010026951 Short-Acting Insulin Proteins 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000005280 amorphization Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- IXIBAKNTJSCKJM-BUBXBXGNSA-N bovine insulin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 IXIBAKNTJSCKJM-BUBXBXGNSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000007654 ischemic lesion Effects 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical group 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000002336 sorption--desorption measurement Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960001726 treprostinil sodium Drugs 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/16—Benz[e]indenes; Hydrogenated benz[e]indenes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Crystallography & Structural Chemistry (AREA)
- Emergency Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本申请公开了曲前列环素的新型盐及其制备方法和用途。
Description
本发明提供曲前列环素的新型盐及其晶形。
曲前列环素(CAS号81846-19-7),其化学名称为(1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-六氢-2-羟基-1-[(3S)-3-羟基辛基]-1H-苯并[f]茚-5-基]氧基]乙酸,具有下式:
它的分子量为390.5,且分子式为C23H34O5。
曲前列环素是Remodulin®、Tyvaso® 和OrenitranTM中的活性成分,适用于治疗肺动脉高压,以减少与运动有关的症状(Remodulin®)和提高运动能力(Tyvaso®和OrenitranTM)。Tyvaso® 和OrenitranTM分别是吸入剂和口服剂型,且Remodulin®适用于皮下或静脉内连续输注使用。
目前批准的曲前列环素制剂包括钠盐和游离酸,但曲前列环素的这些形式的物理和化学稳定性对测试、储存和使用它们的条件敏感,特别是在热稳定性和吸湿性方面,并因此需要特定的方法和设备,包括严格的温度和湿度控制。
因此,需要具有优越性能的曲前列环素的改进形式,其不需要这样的严格的环境控制。
先前已经进行了识别曲前列环素的改进形式的努力。例如,编号为8,252,839的美国专利描述了曲前列环素的二乙醇胺盐,并指出其中描述的化合物比游离酸或盐形式具有增强的口服生物利用度。类似地,编号为8,350,079的美国专利描述了由二乙醇胺盐制备的曲前列环素的一水合物形式,据称其在室温提供了提高的稳定性。最后,编号为9,701,611的美国专利描述了曲前列环素的IA或IIA族金属盐,并指出这样的盐具有提高的溶解度。
然而,仍然需要具有优异物理性能的曲前列环素的新的形式,并且其可以在分析和/或制造环境中进行处理、储存和使用,而无需过度繁琐的环境控制。
由于曲前列环素游离酸和曲前列环素钠盐(曲前列环素的两种最常见的物理形式)对环境条件敏感,因此人们在努力识别具有优异物理性能的曲前列环素形式。发现曲前列环素的特丁胺盐具有出人意料优异的物理性能,包括对水分的敏感性降低且热稳定性提高。特丁胺盐的提高的热稳定性允许在干燥条件下改进的性能,并简化运输、存储和分析。
在一方面,本发明提供了具有以下结构的曲前列环素特丁胺盐:
在另一个实施方案中,本发明提供结晶形式的曲前列环素特丁胺盐,其特征在于获自 CuKα 源(λ = 1.54060 Å)的X射线粉末衍射(XRD)图谱,其包括在5.1°的峰和在10.2°、20.5°和6.8°中至少一处的峰,衍射角公差为0.2°。
在另一个实施方案中,本发明提供结晶形式的曲前列环素特丁胺盐,其特征在于获自 CuKα 源(λ = 1.54060 Å)的XRD图谱,其包括在5.1°和在10.2°、20.5°和6.8°中每一处的峰,衍射角公差为0.2°。
在另一个实施方案中,本发明提供结晶形式的曲前列环素特丁胺盐,其特征在于获自 CuKα 源(λ = 1.54060 Å)的XRD图谱,其包括在5.1°、10.2°、20.5°、6.8°的峰以及13.7°、14.5 °、16.3°、18.7°、19.6°和21.5°中至少一处的峰,衍射角公差为0.2°。
在另一个实施方案中,本发明提供结晶形式的曲前列环素特丁胺盐,其特征在于获自 CuKα 源(λ = 1.54060 Å)的XRD图谱,其包括在5.1°、10.2°、20.5°、6.8°、13.7°、14.5°、16.3°、18.7°、19.6°和21.5°的峰,衍射角公差为0.2°。
在另一方面,本发明提供了药物组合物,其包含任何一种上述曲前列环素特丁胺盐和药学上可接受的载体、赋形剂或稀释剂中的至少一种。
在某些实施方案中,药物组合物还包含具有药理活性的另外的物质。在某些实施方案中,所述具有药理活性的另外的物质是胰岛素。在某些实施方案中,所述胰岛素是赖脯胰岛素(insulin lispro)。
在另一方面,本发明提供了一种在有需要的患者中治疗或预防高血糖的方法,其包括施用治疗有效量的药物组合物,所述药物组合物包含任何一种上述曲前列环素特丁胺盐、至少一种药学上可接受的载体、赋形剂或稀释剂以及胰岛素。
在另一方面,本发明提供了一种在有需要的对象中治疗或预防高血压的方法,其包括施用药学上有效量的任何一种上述曲前列环素特丁胺盐。
在另一方面,本发明提供任何一种上述曲前列环素特丁胺盐在治疗或预防高血压中的用途。
在另一方面,本发明提供任何一种上述曲前列环素特丁胺盐在制备用于治疗或预防高血压的药物中的用途。
在另一方面,本发明提供任何一种上述曲前列环素特丁胺盐作为参考标准用于确定曲前列环素在包含曲前列环素的组合物中的效力中的用途。
在另一方面,本发明提供了制造任何一种上述实施方案中的曲前列环素特丁胺盐的方法,其包括:
a)使曲前列环素游离酸与抗溶剂接触以产生悬浮液;
b)使悬浮液与包含叔丁胺(特丁胺(erbumine))的溶液接触;和
c)分离得到的固体曲前列环素特丁胺盐。
图1:曲前列环素特丁胺的热重分析(TGA)和差示扫描量热法(DSC)热谱图的叠加。
图2:曲前列环素游离酸的热重分析(TGA)和差示扫描量热法(DSC)热谱图的叠加。
图3:曲前列环素特丁胺盐的动态蒸气吸附/再吸收等温线。
图4:曲前列环素钠盐的动态蒸气吸附/再吸收等温线。
如上文所指出的,曲前列环素是经批准用于治疗肺动脉高压的几种产品中的经批准的活性药剂。曲前列环素还被描述用于其他治疗领域,包括改善肾脏功能(参见编号为7,199,157的美国专利)、治疗缺血性病变(参见编号为8,765,813的美国专利)、治疗神经性糖尿病足溃疡(参见编号为8,563,614的美国专利)、治疗间质性肺疾病和哮喘(编号为2014018431的美国申请)和血管病变的治疗(参见编号为2014193379的美国申请)。
曲前列环素还被描述为能够加速胰岛素的时间作用曲线(参见编号为9,439,952的美国专利)。当在本文中使用时,术语“胰岛素”是指人胰岛素、牛胰岛素、猪胰岛素或其任何类似物或衍生物,包括速效胰岛素类似物赖脯胰岛素、门冬胰岛素( insulin aspart)和谷赖胰岛素( insulin glulisine)。
特丁胺(CAS号107133-36-8),也可以称为叔丁胺,具有式(CH3)3CNH2,摩尔质量为73.14,并且具有以下结构:
本发明的曲前列环素特丁胺盐具有以下结构:
应认识到,本发明的曲前列环素特丁胺盐可以适用于上文所描述的任何情况。
另外,鉴于其对水分的敏感性降低,本发明的曲前列环素特丁胺盐也可用作用于分析包含任何形式的曲前列环素的样品的参考标准。
实施例
2-[[(1R,2R,3aS,9aS)-2-羟基-1-[(3S)-3-羟基辛基]-2,3,3a,4,9,9a-六氢-1H-环戊二烯并[g]萘-5-基]氧基]乙酸叔丁胺(曲前列环素特丁胺(Treprostinil erbumine))的制备
在室温搅拌的同时,将曲前列环素游离酸(100 mg)添加到丙酮(2 mL)中。将该悬浮液加热至50℃。在另一个容器中,将叔丁胺(26 mg,1.4当量)与丙酮(1 mL)混合。滴加该碱溶液,并且悬浮液在几分钟内变为溶液,此时间之后形成悬浮液。添加丙酮(1mL),并继续混合2小时。将混合物搅拌并冷却过夜。通过在Whatman纸上真空过滤分离白色固体。将得到的白色固体饼原位风干,得到99mg(83%收率)的标题化合物。
结晶曲前列环素特丁胺的X射线粉末衍射(XRD)
结晶固体的XRD图谱在Bruker D4 Endeavor X射线粉末衍射仪上获得,该仪器配备有CuKα 源 λ = 1.54060 Å 和Vantec检测器,在35 kV和50 mA操作。样品以2θ为4至40°扫描,步长是以2θ为0.008°,扫描速率是0.5秒/步,且具有0.6mm的发散狭缝、5.28的固定防散射狭缝和9.5mm的检测器狭缝。将干粉末装在石英样品架上,并使用载玻片获得光滑的表面。在环境温度和相对湿度下收集晶形的衍射图谱。在晶体学领域中众所周知的是,对于任何给定的晶形,由于诸如晶体形态学和习性的因素所导致的优选取向,衍射峰的相对强度可能会变化。在存在优选取向的影响的地方,峰强度发生了变化,但多晶型物的特征峰位置未变化。参见例如美国药典#23,国家处方集#18,第1843-1844页,1995(The UnitedStates Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995)。此外,在晶体学领域中还众所周知的是,对于任何给定的晶形,角峰位置可能会略有变化。例如,由于分析样品时温度或湿度的变化、样品位移或内标的存在或不存在,峰位置可能移动。在当前情况下,以2θ为±0.2的峰位可变性会考虑这些潜在的变化,而不会影响对所指示晶型的明确识别。可以基于区别峰(以°2θ为单位)(通常是更突出的峰)的任何独特组合来确定晶型。基于在8.853和26.774°2θ处的NIST 675标准峰调整在环境温度和相对湿度下收集的晶形衍射图谱。
如上文所述,通过XRD分析结晶特丁胺盐的制备的样品,其特征为具有如下表1中所述的衍射峰的XRD图谱,特别是在5.1°处具有峰结合在选自10.2°、20.5°和6.8°处的一个或多个峰,衍射角公差为0.2°。
表1:结晶曲前列环素特丁胺的XRD峰
峰 | 角度 (°2-θ) +/- 0.2° | 相对强度 (最强峰的%) |
1 | 5.1 | 100 |
2 | 6.8 | 36.8 |
3 | 10.2 | 55.7 |
4 | 13.7 | 34.3 |
5 | 14.5 | 18.1 |
6 | 16.3 | 17.2 |
7 | 18.7 | 15.2 |
8 | 19.6 | 18.8 |
9 | 20.5 | 42.8 |
10 | 21.5 | 17.2 |
曲前列环素特丁胺盐和游离酸的热表征
通过在TA Instruments TGA-Q5000热重分析仪上进行的热重分析(TGA)和在TAInstruments Q2000差示扫描量热仪上进行的差示扫描量热法(DSC),对按上文所述制备的曲前列环素特丁胺盐和购自化学制品供应公司的曲前列环素游离酸的样品的热稳定性进行分析。
图1(特丁胺盐)和图2(游离酸)显示了25-225℃的TGA热分析图和25-300℃的DSC热分析图的叠加。TGA数据表明,对于特丁胺盐在25-100℃之间的重量损失为0.2318%,对于游离酸在26-70℃之间的重量损失为1.090%。特丁胺盐的DSC数据显示在143.73℃开始的单个吸热事件(可能是熔融或分解),和游离酸的DSC数据显示三个吸热事件(71.17℃、95.57℃和125.15℃),对应于可能的水合物以及至少两种无水晶形。热表征数据表明,特丁胺盐相对于游离酸具有提高的热稳定性,并且在高达至少100℃时是热稳定的。
曲前列环素特丁胺盐和钠盐的吸湿性
在TA Instruments Q5000SA吸附分析仪上进行如上文所述制备的曲前列环素特丁胺盐和从化学制品供应公司购买的曲前列环素钠的吸湿性分析。在25℃在干燥样品上,按5%增加相对湿度直到95%,然后以5%的间隔减小、回到5%的相对湿度,以产生吸湿曲线。在每个增量平衡样品,直到重量百分比变化<0.0100保持5分钟。
图3(特丁胺盐)和4(钠盐)提供了动态蒸气吸附/再吸收等温线。对于钠盐而言,在80%相对湿度点,样品有25%的重量增加,这被归类为非常吸湿的,并且一旦被吸附,直到相对湿度降低至45%RH时才似乎开始水的解吸。对在吸附/解吸过程中不同点收集的样品如上文所述进行了XRD分析,且数据显示,当钠盐暴露于高的相对湿度时,晶形发生变化,随后是当返回到低的相对湿度时变为非晶态或差的结晶状态的不可逆变化。另一方面,出人意料的是,对于特丁胺盐而言,在80%的相对湿度点,样品的重量增加<0.2%,其特征为不吸湿至略吸湿(如《欧洲药典》在线版第9版,专题5.11( European Pharmacopoeia Online,9th edition, monograph 5.11)所述,尽管实验条件与其中所述有所不同)。进行了XRD分析,并且未显示出如钠盐所示的非晶化方面的物理形式变化。这些数据支持了特丁胺盐出人意料缺乏的吸湿性,其允许改善的储存条件以及在环境条件下的效力控制。因此,吸热和吸湿数据均出人意料地表明,特丁胺盐相对于游离酸和钠盐具有显著提高的物理稳定性。
Claims (13)
2.权利要求1的曲前列环素特丁胺盐,其为结晶形式,其特征在于获自 CuKα 源(λ =1.54060 Å)的XRD图谱,其包括在5.1°的峰和在10.2°、20.5°和6.8°中至少一处的峰,衍射角公差为0.2°。
3.权利要求2的曲前列环素特丁胺盐,其中所述XRD图谱包括在10.2°、 20.5°和6.8°中每一处的峰,衍射角公差为0.2°。
4.权利要求3的曲前列环素特丁胺盐,其中所述XRD图谱还包括在13.7°、 14.5°、16.3°、18.7°、19.6°和21.5°中至少一处的峰,衍射角公差为0.2°。
5.权利要求4的曲前列环素特丁胺盐,其中所述XRD图谱还包括在13.7°、 14.5°、16.3°、18.7°、19.6°和21.5°中每一处的峰,衍射角公差为0.2°。
6.药物组合物,其包含权利要求1-4中任一项的曲前列环素特丁胺盐和药学上可接受的载体、赋形剂或稀释剂中的至少一种。
7.权利要求5的药物组合物,其进一步包含具有药理活性的另外的物质。
8.权利要求6的药物组合物,其中所述具有药理活性的另外的物质是胰岛素。
9.权利要求7的药物组合物,其中所述胰岛素是赖脯胰岛素。
10.一种在有需要的对象中治疗或预防高血糖的方法,包括施用药学上有效量的权利要求8的药物组合物。
11.一种在有需要的对象中治疗或预防高血压的方法,包括施用药学上有效量的权利要求1-5中任一项的曲前列环素特丁胺盐。
12.权利要求1-5中任一项的曲前列环素特丁胺盐作为参考标准用于确定曲前列环素在包含曲前列环素的组合物中的效力的用途。
13.一种制造权利要求1-5中任一项的曲前列环素特丁胺盐的方法,其包括:
a)使曲前列环素游离酸与抗溶剂接触以产生悬浮液;
b)使所述悬浮液与包含叔丁胺(特丁胺)的溶液接触;
c)分离得到的固体曲前列环素特丁胺盐。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862732799P | 2018-09-18 | 2018-09-18 | |
US62/732799 | 2018-09-18 | ||
PCT/US2019/050632 WO2020060823A1 (en) | 2018-09-18 | 2019-09-11 | Erbumine salt of treprostinil |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112739679A true CN112739679A (zh) | 2021-04-30 |
CN112739679B CN112739679B (zh) | 2024-03-12 |
Family
ID=68052002
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980060738.8A Active CN112739679B (zh) | 2018-09-18 | 2019-09-11 | 曲前列环素的特丁胺盐 |
Country Status (12)
Country | Link |
---|---|
US (1) | US20220047535A1 (zh) |
EP (1) | EP3853200B1 (zh) |
JP (1) | JP7194817B2 (zh) |
KR (1) | KR102659451B1 (zh) |
CN (1) | CN112739679B (zh) |
AU (1) | AU2019344541B2 (zh) |
BR (1) | BR112021002200B1 (zh) |
CA (1) | CA3112986C (zh) |
EA (1) | EA202190552A1 (zh) |
IL (1) | IL280891A (zh) |
MX (1) | MX2021003090A (zh) |
WO (1) | WO2020060823A1 (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1822826A (zh) * | 2003-05-22 | 2006-08-23 | 联合治疗公司 | 化合物和释放前列环素类似物的方法 |
US20160243064A1 (en) * | 2015-02-21 | 2016-08-25 | Gavis Pharmaceuticals | Novel oral pharmaceutical compositions of treprostinil |
CN107920992A (zh) * | 2015-08-27 | 2018-04-17 | 伊莱利利公司 | 速效胰岛素组合物 |
WO2018106632A1 (en) * | 2016-12-05 | 2018-06-14 | Corsair Pharma, Inc. | Dermal and transdermal administration of treprostinil and salts thereof |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20060123482A (ko) | 2003-12-16 | 2006-12-01 | 유나이티드 쎄러퓨틱스 코포레이션 | 신장 기능을 개선하기 위한 트레프로스티닐의 용도 |
KR101161889B1 (ko) | 2003-12-16 | 2012-07-02 | 유나이티드 쎄러퓨틱스 코포레이션 | 허혈성 병변의 치료 및 예방을 위한 트레프로스티닐의 용도 |
WO2005099680A2 (en) | 2004-04-12 | 2005-10-27 | United Therapeutics, Inc. | Use of treprostinil to treat neuropathic diabetic foot ulcers |
WO2008098196A1 (en) | 2007-02-09 | 2008-08-14 | United Therapeutics Corporation | Treprostinil treatment for interstitial lung disease and asthma |
FR2920772B1 (fr) * | 2007-09-11 | 2009-10-23 | Servier Lab | Association entre un anti-atherothrombotique et un inhibiteur de l'enzyme de conversion de l'angiotensine |
CA2723540C (en) | 2008-05-08 | 2016-01-05 | United Therapeutics Corporation | Treprostinil monohydrate |
CA2726599C (en) * | 2010-12-30 | 2017-07-25 | Alphora Research Inc. | Process for treprostinil salt preparation |
EP2943069B1 (en) | 2013-01-09 | 2018-08-15 | United Therapeutics Corporation | Treatment of vasculopathy with prostacyclin and mesenchymal stem cells |
WO2014150203A1 (en) * | 2013-03-15 | 2014-09-25 | United Therapeutics Corporation | Salts of treprostinil |
KR20160086837A (ko) * | 2013-11-13 | 2016-07-20 | 카이맨 케미칼 컴파니 인코포레이티드 | 프로스타사이클린 유사체의 아민 염 |
TWI685348B (zh) | 2014-05-08 | 2020-02-21 | 美國禮來大藥廠 | 速效胰島素組合物 |
-
2019
- 2019-09-11 EA EA202190552A patent/EA202190552A1/ru unknown
- 2019-09-11 MX MX2021003090A patent/MX2021003090A/es unknown
- 2019-09-11 AU AU2019344541A patent/AU2019344541B2/en active Active
- 2019-09-11 EP EP19773695.2A patent/EP3853200B1/en active Active
- 2019-09-11 CA CA3112986A patent/CA3112986C/en active Active
- 2019-09-11 WO PCT/US2019/050632 patent/WO2020060823A1/en active Application Filing
- 2019-09-11 CN CN201980060738.8A patent/CN112739679B/zh active Active
- 2019-09-11 BR BR112021002200-7A patent/BR112021002200B1/pt active IP Right Grant
- 2019-09-11 KR KR1020217007704A patent/KR102659451B1/ko active IP Right Grant
- 2019-09-11 US US17/274,883 patent/US20220047535A1/en active Pending
- 2019-09-11 JP JP2021515022A patent/JP7194817B2/ja active Active
-
2021
- 2021-02-15 IL IL280891A patent/IL280891A/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1822826A (zh) * | 2003-05-22 | 2006-08-23 | 联合治疗公司 | 化合物和释放前列环素类似物的方法 |
US20160243064A1 (en) * | 2015-02-21 | 2016-08-25 | Gavis Pharmaceuticals | Novel oral pharmaceutical compositions of treprostinil |
CN107920992A (zh) * | 2015-08-27 | 2018-04-17 | 伊莱利利公司 | 速效胰岛素组合物 |
WO2018106632A1 (en) * | 2016-12-05 | 2018-06-14 | Corsair Pharma, Inc. | Dermal and transdermal administration of treprostinil and salts thereof |
Also Published As
Publication number | Publication date |
---|---|
MX2021003090A (es) | 2021-05-12 |
BR112021002200A2 (pt) | 2021-05-04 |
EA202190552A1 (ru) | 2021-06-18 |
US20220047535A1 (en) | 2022-02-17 |
JP7194817B2 (ja) | 2022-12-22 |
BR112021002200B1 (pt) | 2024-03-12 |
KR20210046028A (ko) | 2021-04-27 |
JP2022500468A (ja) | 2022-01-04 |
EP3853200B1 (en) | 2024-01-24 |
WO2020060823A1 (en) | 2020-03-26 |
CA3112986C (en) | 2024-06-18 |
IL280891A (en) | 2021-04-29 |
EP3853200A1 (en) | 2021-07-28 |
CN112739679B (zh) | 2024-03-12 |
KR102659451B1 (ko) | 2024-04-23 |
AU2019344541B2 (en) | 2022-01-06 |
CA3112986A1 (en) | 2020-03-26 |
AU2019344541A1 (en) | 2021-03-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2012308274B2 (en) | Noribogaine salt ansolvates | |
US20050267209A1 (en) | Mixed co-crystals and pharmaceutical compositions comprising the same | |
US20090170945A1 (en) | Pregabalin salts | |
US20240076290A1 (en) | Solid forms of a modulator of hemoglobin | |
US20240124458A1 (en) | Polymorphs of avapritinib and methods for preparing the polymorphs | |
CN112739679B (zh) | 曲前列环素的特丁胺盐 | |
US20080200474A1 (en) | Novel flunarizine salt forms and methods of making and using the same | |
US20220372024A1 (en) | Crystalline forms of entrectinib | |
EA043230B1 (ru) | Эрбуминовая соль трепростинила | |
WO2021001457A1 (en) | Crystalline (r)-2-amino-3-phenylpropylcarbamate acid addition salts | |
WO2024062421A1 (en) | Bexagliflozin in monohydrate, dihydrate or amorphous forms | |
WO2024023796A1 (en) | Polymorphs, co-crystals and solvates of fruquintinib, processes for the preparation and use thereof | |
WO2022238389A2 (en) | Novel forms of entinostat | |
WO2022018450A1 (en) | Crystalline forms of vadadustat and methods for their preparation | |
WO2021028678A1 (en) | Polymorph of venetoclax and method for preparing the polymorph | |
CN113429447A (zh) | 阿糖胞苷前药mb07133晶型e及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |