ES2814157T3 - Formulaciones liofilizadas para antídoto del factor Xa - Google Patents

Formulaciones liofilizadas para antídoto del factor Xa Download PDF

Info

Publication number: ES2814157T3
Authority: ES; Spain
Prior art keywords: formulation; mannitol; arginine; sucrose; seq
Prior art date: 2014-08-20
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.): Active

Application number

ES15834421T

Other languages

English (en)

Spanish (es)

Inventor

Juan Wang

Gregory A Sacha

Phuong M Nguyen

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Portola Pharmaceuticals LLC

Original Assignee

Portola Pharmaceuticals LLC

Priority date (The priority date 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 date listed.)

2014-08-20

Filing date

2015-08-20

Publication date

2021-03-26

2015-08-20 Application filed by Portola Pharmaceuticals LLC filed Critical Portola Pharmaceuticals LLC

2021-03-26 Application granted granted Critical

2021-03-26 Publication of ES2814157T3 publication Critical patent/ES2814157T3/es

Status Active legal-status Critical Current

2035-08-20 Anticipated expiration legal-status Critical

Links

239000000203 mixture Substances 0.000 title claims abstract description 222
238000009472 formulation Methods 0.000 title claims abstract description 175
239000000729 antidote Substances 0.000 title description 111
108010074860 Factor Xa Proteins 0.000 title description 9
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 claims abstract description 143
229930195725 Mannitol Natural products 0.000 claims abstract description 143
239000000594 mannitol Substances 0.000 claims abstract description 143
235000010355 mannitol Nutrition 0.000 claims abstract description 143
239000004475 Arginine Substances 0.000 claims abstract description 121
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 121
229930006000 Sucrose Natural products 0.000 claims abstract description 94
239000005720 sucrose Substances 0.000 claims abstract description 94
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 claims abstract description 92
108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 58
229920001184 polypeptide Polymers 0.000 claims abstract description 55
102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 55
239000013011 aqueous formulation Substances 0.000 claims abstract description 43
125000003275 alpha amino acid group Chemical group 0.000 claims abstract description 24
125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims abstract description 18
239000000243 solution Substances 0.000 claims description 129
229960003121 arginine Drugs 0.000 claims description 120
235000009697 arginine Nutrition 0.000 claims description 120
238000000034 method Methods 0.000 claims description 50
239000003146 anticoagulant agent Substances 0.000 claims description 24
239000012931 lyophilized formulation Substances 0.000 claims description 22
230000000740 bleeding effect Effects 0.000 claims description 21
229940123583 Factor Xa inhibitor Drugs 0.000 claims description 20
229940127219 anticoagulant drug Drugs 0.000 claims description 20
238000002560 therapeutic procedure Methods 0.000 claims description 18
235000001014 amino acid Nutrition 0.000 claims description 16
KWTQSFXGGICVPE-WCCKRBBISA-N Arginine hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CCCN=C(N)N KWTQSFXGGICVPE-WCCKRBBISA-N 0.000 claims description 14
229940024606 amino acid Drugs 0.000 claims description 14
150000001413 amino acids Chemical class 0.000 claims description 14
125000000539 amino acid group Chemical group 0.000 claims description 10
229950011103 betrixaban Drugs 0.000 claims description 9
XHOLNRLADUSQLD-UHFFFAOYSA-N betrixaban Chemical compound C=1C=C(Cl)C=NC=1NC(=O)C1=CC(OC)=CC=C1NC(=O)C1=CC=C(C(=N)N(C)C)C=C1 XHOLNRLADUSQLD-UHFFFAOYSA-N 0.000 claims description 9
229960001148 rivaroxaban Drugs 0.000 claims description 6
KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 claims description 6
QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 claims description 5
229960003886 apixaban Drugs 0.000 claims description 5
230000004048 modification Effects 0.000 claims description 4
238000012986 modification Methods 0.000 claims description 4
239000003125 aqueous solvent Substances 0.000 claims 1
238000004108 freeze drying Methods 0.000 description 79
239000007983 Tris buffer Substances 0.000 description 63
238000002425 crystallisation Methods 0.000 description 50
230000008025 crystallization Effects 0.000 description 50
235000018102 proteins Nutrition 0.000 description 49
102000004169 proteins and genes Human genes 0.000 description 49
108090000623 proteins and genes Proteins 0.000 description 49
KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 47
238000001035 drying Methods 0.000 description 43
238000013456 study Methods 0.000 description 41
239000000872 buffer Substances 0.000 description 38
230000000694 effects Effects 0.000 description 37
235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 29
229920000053 polysorbate 80 Polymers 0.000 description 29
239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 28
229940068968 polysorbate 80 Drugs 0.000 description 28
239000002904 solvent Substances 0.000 description 28
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 26
239000000523 sample Substances 0.000 description 25
238000000113 differential scanning calorimetry Methods 0.000 description 24
235000002639 sodium chloride Nutrition 0.000 description 24
ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 23
239000003112 inhibitor Substances 0.000 description 21
239000007924 injection Substances 0.000 description 20
238000002347 injection Methods 0.000 description 20
208000032843 Hemorrhage Diseases 0.000 description 19
208000034158 bleeding Diseases 0.000 description 19
239000000047 product Substances 0.000 description 19
239000003381 stabilizer Substances 0.000 description 19
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 18
238000000137 annealing Methods 0.000 description 18
239000003814 drug Substances 0.000 description 17
229910019142 PO4 Inorganic materials 0.000 description 16
239000000546 pharmaceutical excipient Substances 0.000 description 16
239000010452 phosphate Substances 0.000 description 16
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 16
239000004094 surface-active agent Substances 0.000 description 16
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
239000011780 sodium chloride Substances 0.000 description 15
239000003795 chemical substances by application Substances 0.000 description 14
235000018417 cysteine Nutrition 0.000 description 14
238000002474 experimental method Methods 0.000 description 14
229940079593 drug Drugs 0.000 description 13
239000001488 sodium phosphate Substances 0.000 description 13
229910000162 sodium phosphate Inorganic materials 0.000 description 13
RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 13
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
239000000126 substance Substances 0.000 description 12
238000011161 development Methods 0.000 description 11
238000007710 freezing Methods 0.000 description 11
230000008014 freezing Effects 0.000 description 11
239000008363 phosphate buffer Substances 0.000 description 11
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 11
HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 10
238000001816 cooling Methods 0.000 description 10
-1 fatty acid esters Chemical class 0.000 description 10
239000000825 pharmaceutical preparation Substances 0.000 description 10
238000001757 thermogravimetry curve Methods 0.000 description 10
238000011282 treatment Methods 0.000 description 10
239000004471 Glycine Substances 0.000 description 9
UHBYWPGGCSDKFX-VKHMYHEASA-N gamma-carboxy-L-glutamic acid Chemical compound OC(=O)[C@@H](N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-VKHMYHEASA-N 0.000 description 9
239000007788 liquid Substances 0.000 description 9
238000000386 microscopy Methods 0.000 description 9
150000003839 salts Chemical class 0.000 description 9
239000007787 solid Substances 0.000 description 9
239000007853 buffer solution Substances 0.000 description 8
230000003197 catalytic effect Effects 0.000 description 8
210000004027 cell Anatomy 0.000 description 8
150000001875 compounds Chemical class 0.000 description 8
XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 8
238000000502 dialysis Methods 0.000 description 8
208000035475 disorder Diseases 0.000 description 8
239000008194 pharmaceutical composition Substances 0.000 description 8
239000003755 preservative agent Substances 0.000 description 8
238000012360 testing method Methods 0.000 description 8
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 7
208000007536 Thrombosis Diseases 0.000 description 7
230000002776 aggregation Effects 0.000 description 7
238000004220 aggregation Methods 0.000 description 7
238000012512 characterization method Methods 0.000 description 7
238000001938 differential scanning calorimetry curve Methods 0.000 description 7
238000004128 high performance liquid chromatography Methods 0.000 description 7
238000004519 manufacturing process Methods 0.000 description 7
229940068196 placebo Drugs 0.000 description 7
239000000902 placebo Substances 0.000 description 7
238000001556 precipitation Methods 0.000 description 7
230000001225 therapeutic effect Effects 0.000 description 7
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
229940075522 antidotes Drugs 0.000 description 6
150000001945 cysteines Chemical class 0.000 description 6
238000004090 dissolution Methods 0.000 description 6
239000011521 glass Substances 0.000 description 6
238000011068 loading method Methods 0.000 description 6
239000000463 material Substances 0.000 description 6
229940127557 pharmaceutical product Drugs 0.000 description 6
230000002441 reversible effect Effects 0.000 description 6
238000002076 thermal analysis method Methods 0.000 description 6
FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 5
KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 5
239000004472 Lysine Substances 0.000 description 5
241000124008 Mammalia Species 0.000 description 5
239000004480 active ingredient Substances 0.000 description 5
238000004458 analytical method Methods 0.000 description 5
239000003963 antioxidant agent Substances 0.000 description 5
235000006708 antioxidants Nutrition 0.000 description 5
229960003589 arginine hydrochloride Drugs 0.000 description 5
239000004067 bulking agent Substances 0.000 description 5
238000006243 chemical reaction Methods 0.000 description 5
238000001914 filtration Methods 0.000 description 5
229920000669 heparin Polymers 0.000 description 5
238000001727 in vivo Methods 0.000 description 5
230000005764 inhibitory process Effects 0.000 description 5
239000003055 low molecular weight heparin Substances 0.000 description 5
229940127215 low-molecular weight heparin Drugs 0.000 description 5
238000005259 measurement Methods 0.000 description 5
230000035772 mutation Effects 0.000 description 5
238000007254 oxidation reaction Methods 0.000 description 5
230000004481 post-translational protein modification Effects 0.000 description 5
230000008569 process Effects 0.000 description 5
108010014806 prothrombinase complex Proteins 0.000 description 5
230000002829 reductive effect Effects 0.000 description 5
230000000087 stabilizing effect Effects 0.000 description 5
238000001356 surgical procedure Methods 0.000 description 5
238000012546 transfer Methods 0.000 description 5
HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
108010014173 Factor X Proteins 0.000 description 4
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
108010094028 Prothrombin Proteins 0.000 description 4
102100027378 Prothrombin Human genes 0.000 description 4
HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 4
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 4
229940127090 anticoagulant agent Drugs 0.000 description 4
238000013459 approach Methods 0.000 description 4
238000013461 design Methods 0.000 description 4
235000014113 dietary fatty acids Nutrition 0.000 description 4
201000010099 disease Diseases 0.000 description 4
239000003937 drug carrier Substances 0.000 description 4
230000002255 enzymatic effect Effects 0.000 description 4
239000000194 fatty acid Substances 0.000 description 4
229930195729 fatty acid Natural products 0.000 description 4
230000004907 flux Effects 0.000 description 4
239000012537 formulation buffer Substances 0.000 description 4
238000000338 in vitro Methods 0.000 description 4
230000002401 inhibitory effect Effects 0.000 description 4
239000012528 membrane Substances 0.000 description 4
230000002947 procoagulating effect Effects 0.000 description 4
230000006920 protein precipitation Effects 0.000 description 4
229940039716 prothrombin Drugs 0.000 description 4
238000003860 storage Methods 0.000 description 4
235000000346 sugar Nutrition 0.000 description 4
208000024891 symptom Diseases 0.000 description 4
SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 3
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
239000004255 Butylated hydroxyanisole Substances 0.000 description 3
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
241001465754 Metazoa Species 0.000 description 3
229920001214 Polysorbate 60 Polymers 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
108010022999 Serine Proteases Proteins 0.000 description 3
102000012479 Serine Proteases Human genes 0.000 description 3
108090000190 Thrombin Proteins 0.000 description 3
239000013543 active substance Substances 0.000 description 3
235000010323 ascorbic acid Nutrition 0.000 description 3
239000011668 ascorbic acid Substances 0.000 description 3
230000000903 blocking effect Effects 0.000 description 3
210000004369 blood Anatomy 0.000 description 3
239000008280 blood Substances 0.000 description 3
239000012512 bulk drug substance Substances 0.000 description 3
239000008364 bulk solution Substances 0.000 description 3
235000019282 butylated hydroxyanisole Nutrition 0.000 description 3
230000008859 change Effects 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
238000009295 crossflow filtration Methods 0.000 description 3
239000002577 cryoprotective agent Substances 0.000 description 3
230000003247 decreasing effect Effects 0.000 description 3
229960000610 enoxaparin Drugs 0.000 description 3
238000011156 evaluation Methods 0.000 description 3
KANJSNBRCNMZMV-ABRZTLGGSA-N fondaparinux Chemical compound O[C@@H]1[C@@H](NS(O)(=O)=O)[C@@H](OC)O[C@H](COS(O)(=O)=O)[C@H]1O[C@H]1[C@H](OS(O)(=O)=O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O4)NS(O)(=O)=O)[C@H](O3)C(O)=O)O)[C@@H](COS(O)(=O)=O)O2)NS(O)(=O)=O)[C@H](C(O)=O)O1 KANJSNBRCNMZMV-ABRZTLGGSA-N 0.000 description 3
230000004927 fusion Effects 0.000 description 3
230000009477 glass transition Effects 0.000 description 3
235000011187 glycerol Nutrition 0.000 description 3
230000013595 glycosylation Effects 0.000 description 3
238000006206 glycosylation reaction Methods 0.000 description 3
HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
230000003993 interaction Effects 0.000 description 3
238000001990 intravenous administration Methods 0.000 description 3
230000007774 longterm Effects 0.000 description 3
230000014759 maintenance of location Effects 0.000 description 3
239000011159 matrix material Substances 0.000 description 3
238000001565 modulated differential scanning calorimetry Methods 0.000 description 3
230000014508 negative regulation of coagulation Effects 0.000 description 3
230000003647 oxidation Effects 0.000 description 3
239000002245 particle Substances 0.000 description 3
239000012071 phase Substances 0.000 description 3
210000002381 plasma Anatomy 0.000 description 3
229920000642 polymer Polymers 0.000 description 3
229920000136 polysorbate Polymers 0.000 description 3
238000002360 preparation method Methods 0.000 description 3
230000002335 preservative effect Effects 0.000 description 3
239000003805 procoagulant Substances 0.000 description 3
230000009467 reduction Effects 0.000 description 3
239000012925 reference material Substances 0.000 description 3
238000004007 reversed phase HPLC Methods 0.000 description 3
229960004072 thrombin Drugs 0.000 description 3
NPBKHEMDWREFJJ-UHFFFAOYSA-N 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(1-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(N(CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)S(=O)(=O)CC(O)=O)C=C1 NPBKHEMDWREFJJ-UHFFFAOYSA-N 0.000 description 2
239000004322 Butylated hydroxytoluene Substances 0.000 description 2
229920002307 Dextran Polymers 0.000 description 2
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 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
HGVDHZBSSITLCT-JLJPHGGASA-N Edoxaban Chemical compound N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 HGVDHZBSSITLCT-JLJPHGGASA-N 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
KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
229920001213 Polysorbate 20 Polymers 0.000 description 2
WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
BGNXCDMCOKJUMV-UHFFFAOYSA-N Tert-Butylhydroquinone Chemical compound CC(C)(C)C1=CC(O)=CC=C1O BGNXCDMCOKJUMV-UHFFFAOYSA-N 0.000 description 2
102100030951 Tissue factor pathway inhibitor Human genes 0.000 description 2
229960002054 acenocoumarol Drugs 0.000 description 2
VABCILAOYCMVPS-UHFFFAOYSA-N acenocoumarol Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=C([N+]([O-])=O)C=C1 VABCILAOYCMVPS-UHFFFAOYSA-N 0.000 description 2
230000003213 activating effect Effects 0.000 description 2
150000005215 alkyl ethers Chemical class 0.000 description 2
229940075564 anhydrous dibasic sodium phosphate Drugs 0.000 description 2
230000000845 anti-microbial effect Effects 0.000 description 2
229960005070 ascorbic acid Drugs 0.000 description 2
230000008901 benefit Effects 0.000 description 2
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
108010055460 bivalirudin Proteins 0.000 description 2
OIRCOABEOLEUMC-GEJPAHFPSA-N bivalirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OIRCOABEOLEUMC-GEJPAHFPSA-N 0.000 description 2
235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
238000003776 cleavage reaction Methods 0.000 description 2
239000012141 concentrate Substances 0.000 description 2
IJNIQYINMSGIPS-UHFFFAOYSA-N darexaban Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=CC(O)=C1NC(=O)C1=CC=C(N2CCN(C)CCC2)C=C1 IJNIQYINMSGIPS-UHFFFAOYSA-N 0.000 description 2
230000007423 decrease Effects 0.000 description 2
239000002270 dispersing agent Substances 0.000 description 2
239000013583 drug formulation Substances 0.000 description 2
229940126534 drug product Drugs 0.000 description 2
229960000622 edoxaban Drugs 0.000 description 2
239000003995 emulsifying agent Substances 0.000 description 2
QQBKAVAGLMGMHI-WIYYLYMNSA-N eribaxaban Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C=CC=C1)=O)F)C(=O)NC1=CC=C(Cl)C=C1 QQBKAVAGLMGMHI-WIYYLYMNSA-N 0.000 description 2
150000002170 ethers Chemical class 0.000 description 2
229960001318 fondaparinux Drugs 0.000 description 2
229940087051 fragmin Drugs 0.000 description 2
238000013457 freeze/thaw-study Methods 0.000 description 2
239000008103 glucose Substances 0.000 description 2
230000023597 hemostasis Effects 0.000 description 2
229960002897 heparin Drugs 0.000 description 2
239000004615 ingredient Substances 0.000 description 2
208000014674 injury Diseases 0.000 description 2
FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 2
FIBJDTSHOUXTKV-BRHMIFOHSA-N lepirudin Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)CNC2=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)[C@@H](C)O)[C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N1)C(C)C)C(C)C)[C@@H](C)O)[C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O FIBJDTSHOUXTKV-BRHMIFOHSA-N 0.000 description 2
108010013555 lipoprotein-associated coagulation inhibitor Proteins 0.000 description 2
238000012792 lyophilization process Methods 0.000 description 2
RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
238000012544 monitoring process Methods 0.000 description 2
210000004985 myeloid-derived suppressor cell Anatomy 0.000 description 2
VYNKVNDKAOGAAQ-RUZDIDTESA-N n-[(1r)-2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxo-1-phenylethyl]-1h-indole-6-carboxamide Chemical compound C1CN(C)CCC1N1CCN(C(=O)[C@H](NC(=O)C=2C=C3NC=CC3=CC=2)C=2C=CC=CC=2)CC1 VYNKVNDKAOGAAQ-RUZDIDTESA-N 0.000 description 2
MVPQUSQUURLQKF-MCPDASDXSA-E nonasodium;(2s,3s,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3s,4s,5r,6r)-2-carboxylato-4,5-dimethoxy-6-[(2r,3r,4s,5r,6s)-6-methoxy-4,5-disulfonatooxy-2-(sulfonatooxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-disulfonatooxy-2-(sulfonatooxymethyl)oxan-3-yl]oxy-4,5-di Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]S(=O)(=O)O[C@@H]1[C@@H](OS([O-])(=O)=O)[C@@H](OC)O[C@H](COS([O-])(=O)=O)[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@@H]2[C@@H]([C@@H](OS([O-])(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](OC)[C@H](O[C@@H]4[C@@H]([C@@H](OC)[C@H](OC)[C@@H](COS([O-])(=O)=O)O4)OC)[C@H](O3)C([O-])=O)OC)[C@@H](COS([O-])(=O)=O)O2)OS([O-])(=O)=O)[C@H](C([O-])=O)O1 MVPQUSQUURLQKF-MCPDASDXSA-E 0.000 description 2
229920002113 octoxynol Polymers 0.000 description 2
PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 2
229950009478 otamixaban Drugs 0.000 description 2
230000036961 partial effect Effects 0.000 description 2
230000007170 pathology Effects 0.000 description 2
239000000816 peptidomimetic Substances 0.000 description 2
229920001993 poloxamer 188 Polymers 0.000 description 2
229920001223 polyethylene glycol Polymers 0.000 description 2
239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
239000002243 precursor Substances 0.000 description 2
239000000473 propyl gallate Substances 0.000 description 2
235000010388 propyl gallate Nutrition 0.000 description 2
230000004845 protein aggregation Effects 0.000 description 2
150000003254 radicals Chemical class 0.000 description 2
239000012488 sample solution Substances 0.000 description 2
230000007017 scission Effects 0.000 description 2
238000012216 screening Methods 0.000 description 2
238000000926 separation method Methods 0.000 description 2
210000002966 serum Anatomy 0.000 description 2
238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 2
230000003381 solubilizing effect Effects 0.000 description 2
239000011550 stock solution Substances 0.000 description 2
238000006467 substitution reaction Methods 0.000 description 2
239000000758 substrate Substances 0.000 description 2
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
125000000185 sucrose group Chemical group 0.000 description 2
150000008163 sugars Chemical class 0.000 description 2
239000006228 supernatant Substances 0.000 description 2
239000004250 tert-Butylhydroquinone Substances 0.000 description 2
239000012929 tonicity agent Substances 0.000 description 2
230000007704 transition Effects 0.000 description 2
238000000041 tunable diode laser absorption spectroscopy Methods 0.000 description 2
229940019333 vitamin k antagonists Drugs 0.000 description 2
PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 2
239000000080 wetting agent Substances 0.000 description 2
QZNNVYOVQUKYSC-JEDNCBNOSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;hydron;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CN=CN1 QZNNVYOVQUKYSC-JEDNCBNOSA-N 0.000 description 1
LJCBAPRMNYSDOP-LVCYMWGESA-N (2s)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3s)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid;hydron;chloride;pentahydrate Chemical compound O.O.O.O.O.Cl.C1N(C(=N)C)CC[C@@H]1OC1=CC=C([C@H](CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 LJCBAPRMNYSDOP-LVCYMWGESA-N 0.000 description 1
HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 1
GEHAEMCVKDPMKO-HXUWFJFHSA-N 1-[1-[(2s)-3-(6-chloronaphthalen-2-yl)sulfonyl-2-hydroxypropanoyl]piperidin-4-yl]-1,3-diazinan-2-one Chemical compound O=C([C@@H](CS(=O)(=O)C=1C=C2C=CC(Cl)=CC2=CC=1)O)N(CC1)CCC1N1CCCNC1=O GEHAEMCVKDPMKO-HXUWFJFHSA-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
CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
WYMDDFRYORANCC-UHFFFAOYSA-N 2-[[3-[bis(carboxymethyl)amino]-2-hydroxypropyl]-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)CN(CC(O)=O)CC(O)=O WYMDDFRYORANCC-UHFFFAOYSA-N 0.000 description 1
GHCZTIFQWKKGSB-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;phosphoric acid Chemical compound OP(O)(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O GHCZTIFQWKKGSB-UHFFFAOYSA-N 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
101800001401 Activation peptide Proteins 0.000 description 1
102400000069 Activation peptide Human genes 0.000 description 1
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 1
238000012371 Aseptic Filling Methods 0.000 description 1
241000894006 Bacteria Species 0.000 description 1
239000005711 Benzoic acid Substances 0.000 description 1
241000283690 Bos taurus Species 0.000 description 1
NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
241000282472 Canis lupus familiaris Species 0.000 description 1
GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
108090000317 Chymotrypsin Proteins 0.000 description 1
YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
208000034656 Contusions Diseases 0.000 description 1
229920000858 Cyclodextrin Polymers 0.000 description 1
FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
JYGLAHSAISAEAL-UHFFFAOYSA-N Diphenadione Chemical compound O=C1C2=CC=CC=C2C(=O)C1C(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 JYGLAHSAISAEAL-UHFFFAOYSA-N 0.000 description 1
229940123688 Direct Factor Xa inhibitor Drugs 0.000 description 1
239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
206010013496 Disturbance in attention Diseases 0.000 description 1
102000004190 Enzymes Human genes 0.000 description 1
108090000790 Enzymes Proteins 0.000 description 1
CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
108010048049 Factor IXa Proteins 0.000 description 1
108010054265 Factor VIIa Proteins 0.000 description 1
108010071241 Factor XIIa Proteins 0.000 description 1
108010080805 Factor XIa Proteins 0.000 description 1
241000233866 Fungi Species 0.000 description 1
206010055847 Haemorrhage urinary tract Diseases 0.000 description 1
108010007267 Hirudins Proteins 0.000 description 1
102000007625 Hirudins Human genes 0.000 description 1
241000282412 Homo Species 0.000 description 1
101001024703 Homo sapiens Nck-associated protein 5 Proteins 0.000 description 1
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
229940122093 Indirect Factor Xa inhibitor Drugs 0.000 description 1
238000003109 Karl Fischer titration Methods 0.000 description 1
HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
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 1
239000012901 Milli-Q water Substances 0.000 description 1
241000699670 Mus sp. Species 0.000 description 1
102100036946 Nck-associated protein 5 Human genes 0.000 description 1
241000283973 Oryctolagus cuniculus Species 0.000 description 1
229940123973 Oxygen scavenger Drugs 0.000 description 1
101800004937 Protein C Proteins 0.000 description 1
241000700159 Rattus Species 0.000 description 1
206010038063 Rectal haemorrhage Diseases 0.000 description 1
101800001700 Saposin-D Proteins 0.000 description 1
102400000827 Saposin-D Human genes 0.000 description 1
DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 description 1
229940122388 Thrombin inhibitor Drugs 0.000 description 1
108090000631 Trypsin Proteins 0.000 description 1
102000004142 Trypsin Human genes 0.000 description 1
208000027418 Wounds and injury Diseases 0.000 description 1
238000002835 absorbance Methods 0.000 description 1
239000006096 absorbing agent Substances 0.000 description 1
239000002253 acid Substances 0.000 description 1
239000000654 additive Substances 0.000 description 1
239000002671 adjuvant Substances 0.000 description 1
230000002411 adverse Effects 0.000 description 1
229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
150000008052 alkyl sulfonates Chemical class 0.000 description 1
230000004075 alteration Effects 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
150000001412 amines Chemical class 0.000 description 1
229940003354 angiomax Drugs 0.000 description 1
125000000129 anionic group Chemical group 0.000 description 1
239000003945 anionic surfactant Substances 0.000 description 1
230000002429 anti-coagulating effect Effects 0.000 description 1
230000002785 anti-thrombosis Effects 0.000 description 1
230000003078 antioxidant effect Effects 0.000 description 1
229960004676 antithrombotic agent Drugs 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 1
229960003856 argatroban Drugs 0.000 description 1
125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
229940104697 arixtra Drugs 0.000 description 1
125000003118 aryl group Chemical group 0.000 description 1
238000003556 assay Methods 0.000 description 1
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
230000004888 barrier function Effects 0.000 description 1
229960000686 benzalkonium chloride Drugs 0.000 description 1
235000010233 benzoic acid Nutrition 0.000 description 1
229960004365 benzoic acid Drugs 0.000 description 1
CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
238000005842 biochemical reaction Methods 0.000 description 1
230000004071 biological effect Effects 0.000 description 1
230000008033 biological extinction Effects 0.000 description 1
239000012620 biological material Substances 0.000 description 1
239000012472 biological sample Substances 0.000 description 1
230000015572 biosynthetic process Effects 0.000 description 1
229960001500 bivalirudin Drugs 0.000 description 1
230000023555 blood coagulation Effects 0.000 description 1
KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
229940043253 butylated hydroxyanisole Drugs 0.000 description 1
CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
229940095259 butylated hydroxytoluene Drugs 0.000 description 1
210000004899 c-terminal region Anatomy 0.000 description 1
150000001720 carbohydrates Chemical class 0.000 description 1
235000014633 carbohydrates Nutrition 0.000 description 1
230000015556 catabolic process Effects 0.000 description 1
125000002091 cationic group Chemical group 0.000 description 1
239000003093 cationic surfactant Substances 0.000 description 1
239000001913 cellulose Substances 0.000 description 1
229920002678 cellulose Polymers 0.000 description 1
235000010980 cellulose Nutrition 0.000 description 1
239000002738 chelating agent Substances 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
239000003638 chemical reducing agent Substances 0.000 description 1
229960003260 chlorhexidine Drugs 0.000 description 1
229960004926 chlorobutanol Drugs 0.000 description 1
229960002376 chymotrypsin Drugs 0.000 description 1
239000007979 citrate buffer Substances 0.000 description 1
229960004106 citric acid Drugs 0.000 description 1
150000001860 citric acid derivatives Chemical class 0.000 description 1
229960002303 citric acid monohydrate Drugs 0.000 description 1
229960001307 clorindione Drugs 0.000 description 1
NJDUWAXIURWWLN-UHFFFAOYSA-N clorindione Chemical compound C1=CC(Cl)=CC=C1C1C(=O)C2=CC=CC=C2C1=O NJDUWAXIURWWLN-UHFFFAOYSA-N 0.000 description 1
230000035602 clotting Effects 0.000 description 1
238000007820 coagulation assay Methods 0.000 description 1
239000008139 complexing agent Substances 0.000 description 1
230000021615 conjugation Effects 0.000 description 1
239000000356 contaminant Substances 0.000 description 1
229920001577 copolymer Polymers 0.000 description 1
229940072645 coumadin Drugs 0.000 description 1
229940097362 cyclodextrins Drugs 0.000 description 1
229960004969 dalteparin Drugs 0.000 description 1
230000006378 damage Effects 0.000 description 1
229960003828 danaparoid Drugs 0.000 description 1
238000000354 decomposition reaction Methods 0.000 description 1
238000006731 degradation reaction Methods 0.000 description 1
230000003111 delayed effect Effects 0.000 description 1
238000012217 deletion Methods 0.000 description 1
230000037430 deletion Effects 0.000 description 1
238000003795 desorption Methods 0.000 description 1
238000001514 detection method Methods 0.000 description 1
239000003599 detergent Substances 0.000 description 1
230000001627 detrimental effect Effects 0.000 description 1
238000011026 diafiltration Methods 0.000 description 1
238000003745 diagnosis Methods 0.000 description 1
239000000385 dialysis solution Substances 0.000 description 1
229960001912 dicoumarol Drugs 0.000 description 1
DOBMPNYZJYQDGZ-UHFFFAOYSA-N dicoumarol Chemical compound C1=CC=CC2=C1OC(=O)C(CC=1C(OC3=CC=CC=C3C=1O)=O)=C2O DOBMPNYZJYQDGZ-UHFFFAOYSA-N 0.000 description 1
238000009792 diffusion process Methods 0.000 description 1
230000029087 digestion Effects 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
OGGXGZAMXPVRFZ-UHFFFAOYSA-M dimethylarsinate Chemical compound C[As](C)([O-])=O OGGXGZAMXPVRFZ-UHFFFAOYSA-M 0.000 description 1
229960000267 diphenadione Drugs 0.000 description 1
LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
229940019332 direct factor xa inhibitors Drugs 0.000 description 1
235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
238000002296 dynamic light scattering Methods 0.000 description 1
230000001804 emulsifying effect Effects 0.000 description 1
238000005516 engineering process Methods 0.000 description 1
229940088598 enzyme Drugs 0.000 description 1
208000001780 epistaxis Diseases 0.000 description 1
238000011067 equilibration Methods 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
229960002822 ethyl biscoumacetate Drugs 0.000 description 1
SEGSDVUVOWIWFX-UHFFFAOYSA-N ethyl biscoumacetate Chemical compound C1=CC=C2C(=O)C(C(C=3C(C4=CC=CC=C4OC=3O)=O)C(=O)OCC)=C(O)OC2=C1 SEGSDVUVOWIWFX-UHFFFAOYSA-N 0.000 description 1
230000005713 exacerbation Effects 0.000 description 1
230000001747 exhibiting effect Effects 0.000 description 1
229940012414 factor viia Drugs 0.000 description 1
150000004665 fatty acids Chemical class 0.000 description 1
238000011049 filling Methods 0.000 description 1
239000004088 foaming agent Substances 0.000 description 1
235000013305 food Nutrition 0.000 description 1
238000012395 formulation development Methods 0.000 description 1
238000002523 gelfiltration Methods 0.000 description 1
229960005150 glycerol Drugs 0.000 description 1
239000008187 granular material Substances 0.000 description 1
230000036541 health Effects 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
230000000004 hemodynamic effect Effects 0.000 description 1
208000031169 hemorrhagic disease Diseases 0.000 description 1
WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 1
229940006607 hirudin Drugs 0.000 description 1
125000001183 hydrocarbyl group Chemical group 0.000 description 1
238000000099 in vitro assay Methods 0.000 description 1
230000002452 interceptive effect Effects 0.000 description 1
239000000543 intermediate Substances 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
238000004255 ion exchange chromatography Methods 0.000 description 1
125000003010 ionic group Chemical group 0.000 description 1
150000002500 ions Chemical class 0.000 description 1
238000002955 isolation Methods 0.000 description 1
238000002372 labelling Methods 0.000 description 1
239000008101 lactose Substances 0.000 description 1
239000000787 lecithin Substances 0.000 description 1
235000010445 lecithin Nutrition 0.000 description 1
229940067606 lecithin Drugs 0.000 description 1
108010002230 lepirudin Proteins 0.000 description 1
229960004408 lepirudin Drugs 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
239000007791 liquid phase Substances 0.000 description 1
229940118179 lovenox Drugs 0.000 description 1
231100000053 low toxicity Toxicity 0.000 description 1
239000002075 main ingredient Substances 0.000 description 1
238000012423 maintenance Methods 0.000 description 1
239000003550 marker Substances 0.000 description 1
230000001404 mediated effect Effects 0.000 description 1
229930182817 methionine Natural products 0.000 description 1
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
229960002216 methylparaben Drugs 0.000 description 1
230000000813 microbial effect Effects 0.000 description 1
238000006386 neutralization reaction Methods 0.000 description 1
230000003472 neutralizing effect Effects 0.000 description 1
239000002736 nonionic surfactant Substances 0.000 description 1
239000002773 nucleotide Substances 0.000 description 1
125000003729 nucleotide group Chemical group 0.000 description 1
230000003287 optical effect Effects 0.000 description 1
210000000056 organ Anatomy 0.000 description 1
230000003204 osmotic effect Effects 0.000 description 1
238000007500 overflow downdraw method Methods 0.000 description 1
239000007800 oxidant agent Substances 0.000 description 1
230000001590 oxidative effect Effects 0.000 description 1
229910052760 oxygen Inorganic materials 0.000 description 1
239000001301 oxygen Substances 0.000 description 1
239000003973 paint Substances 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
230000037361 pathway Effects 0.000 description 1
230000002085 persistent effect Effects 0.000 description 1
239000008180 pharmaceutical surfactant Substances 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
229960000280 phenindione Drugs 0.000 description 1
NFBAXHOPROOJAW-UHFFFAOYSA-N phenindione Chemical compound O=C1C2=CC=CC=C2C(=O)C1C1=CC=CC=C1 NFBAXHOPROOJAW-UHFFFAOYSA-N 0.000 description 1
229960003742 phenol Drugs 0.000 description 1
229960004923 phenprocoumon Drugs 0.000 description 1
DQDAYGNAKTZFIW-UHFFFAOYSA-N phenprocoumon Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC)C1=CC=CC=C1 DQDAYGNAKTZFIW-UHFFFAOYSA-N 0.000 description 1
WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
239000002953 phosphate buffered saline Substances 0.000 description 1
150000003904 phospholipids Chemical class 0.000 description 1
230000001766 physiological effect Effects 0.000 description 1
239000002504 physiological saline solution Substances 0.000 description 1
210000004623 platelet-rich plasma Anatomy 0.000 description 1
229920001983 poloxamer Polymers 0.000 description 1
229940044519 poloxamer 188 Drugs 0.000 description 1
229920000058 polyacrylate Polymers 0.000 description 1
229920000193 polymethacrylate Polymers 0.000 description 1
229920005862 polyol Polymers 0.000 description 1
150000003077 polyols Chemical class 0.000 description 1
229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
150000008442 polyphenolic compounds Chemical class 0.000 description 1
235000013824 polyphenols Nutrition 0.000 description 1
229920001451 polypropylene glycol Polymers 0.000 description 1
229950008882 polysorbate Drugs 0.000 description 1
229940068977 polysorbate 20 Drugs 0.000 description 1
229920002451 polyvinyl alcohol Polymers 0.000 description 1
235000019422 polyvinyl alcohol Nutrition 0.000 description 1
239000001267 polyvinylpyrrolidone Substances 0.000 description 1
238000011176 pooling Methods 0.000 description 1
DJEHXEMURTVAOE-UHFFFAOYSA-M potassium bisulfite Chemical compound [K+].OS([O-])=O DJEHXEMURTVAOE-UHFFFAOYSA-M 0.000 description 1
239000001103 potassium chloride Substances 0.000 description 1
235000011164 potassium chloride Nutrition 0.000 description 1
235000010259 potassium hydrogen sulphite Nutrition 0.000 description 1
235000010241 potassium sorbate Nutrition 0.000 description 1
239000004302 potassium sorbate Substances 0.000 description 1
229940069338 potassium sorbate Drugs 0.000 description 1
239000012254 powdered material Substances 0.000 description 1
238000004321 preservation Methods 0.000 description 1
230000002265 prevention Effects 0.000 description 1
230000002062 proliferating effect Effects 0.000 description 1
230000001737 promoting effect Effects 0.000 description 1
230000000069 prophylactic effect Effects 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
229940075579 propyl gallate Drugs 0.000 description 1
239000003223 protective agent Substances 0.000 description 1
229960000856 protein c Drugs 0.000 description 1
239000012460 protein solution Substances 0.000 description 1
238000000746 purification Methods 0.000 description 1
239000008213 purified water Substances 0.000 description 1
230000009257 reactivity Effects 0.000 description 1
230000000306 recurrent effect Effects 0.000 description 1
229940030915 refludan Drugs 0.000 description 1
238000009877 rendering Methods 0.000 description 1
230000002000 scavenging effect Effects 0.000 description 1
230000028327 secretion Effects 0.000 description 1
230000035945 sensitivity Effects 0.000 description 1
239000011734 sodium Substances 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
239000001509 sodium citrate Substances 0.000 description 1
NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical group O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
239000011343 solid material Substances 0.000 description 1
239000000600 sorbitol Substances 0.000 description 1
229940124547 specific antidotes Drugs 0.000 description 1
238000004611 spectroscopical analysis Methods 0.000 description 1
230000002269 spontaneous effect Effects 0.000 description 1
230000001954 sterilising effect Effects 0.000 description 1
238000004659 sterilization and disinfection Methods 0.000 description 1
238000003756 stirring Methods 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
238000000859 sublimation Methods 0.000 description 1
230000008022 sublimation Effects 0.000 description 1
239000008362 succinate buffer Substances 0.000 description 1
LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
235000010269 sulphur dioxide Nutrition 0.000 description 1
230000009885 systemic effect Effects 0.000 description 1
WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
235000019281 tert-butylhydroquinone Nutrition 0.000 description 1
238000010257 thawing Methods 0.000 description 1
238000011285 therapeutic regimen Methods 0.000 description 1
RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
229940033663 thimerosal Drugs 0.000 description 1
150000003573 thiols Chemical class 0.000 description 1
238000012032 thrombin generation assay Methods 0.000 description 1
239000003868 thrombin inhibitor Substances 0.000 description 1
229960005062 tinzaparin Drugs 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
229930003799 tocopherol Natural products 0.000 description 1
239000011732 tocopherol Substances 0.000 description 1
125000002640 tocopherol group Chemical class 0.000 description 1
239000000541 tocopherol-rich extract Substances 0.000 description 1
235000019149 tocopherols Nutrition 0.000 description 1
239000011573 trace mineral Substances 0.000 description 1
235000013619 trace mineral Nutrition 0.000 description 1
230000008733 trauma Effects 0.000 description 1
JLEXUIVKURIPFI-UHFFFAOYSA-N tris phosphate Chemical compound OP(O)(O)=O.OCC(N)(CO)CO JLEXUIVKURIPFI-UHFFFAOYSA-N 0.000 description 1
239000012588 trypsin Substances 0.000 description 1
239000011123 type I (borosilicate glass) Substances 0.000 description 1
238000000108 ultra-filtration Methods 0.000 description 1
238000003828 vacuum filtration Methods 0.000 description 1
230000004865 vascular response Effects 0.000 description 1
229960005080 warfarin Drugs 0.000 description 1
238000009736 wetting Methods 0.000 description 1
239000002023 wood Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6432—Coagulation factor Xa (3.4.21.6)
- 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
- A61K38/36—Blood coagulation or fibrinolysis factors
- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21006—Coagulation factor Xa (3.4.21.6)

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Engineering & Computer Science (AREA)
Medicinal Chemistry (AREA)
Animal Behavior & Ethology (AREA)
Pharmacology & Pharmacy (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Epidemiology (AREA)
Bioinformatics & Cheminformatics (AREA)
Organic Chemistry (AREA)
Genetics & Genomics (AREA)
Biochemistry (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Zoology (AREA)
Wood Science & Technology (AREA)
Molecular Biology (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Gastroenterology & Hepatology (AREA)
Oil, Petroleum & Natural Gas (AREA)
Biomedical Technology (AREA)
General Engineering & Computer Science (AREA)
Immunology (AREA)
Microbiology (AREA)
Biotechnology (AREA)
Dermatology (AREA)
Hematology (AREA)
Biophysics (AREA)
Diabetes (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Medicinal Preparation (AREA)
Peptides Or Proteins (AREA)

ES15834421T 2014-08-20 2015-08-20 Formulaciones liofilizadas para antídoto del factor Xa Active ES2814157T3 (es)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US201462039809P	2014-08-20	2014-08-20
PCT/US2015/046173 WO2016029061A1 (en)	2014-08-20	2015-08-20	Lyophilized formulations for factor xa antidote

Publications (1)

Publication Number	Publication Date
ES2814157T3 true ES2814157T3 (es)	2021-03-26

Family

ID=55351266

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
ES15834421T Active ES2814157T3 (es)	2014-08-20	2015-08-20	Formulaciones liofilizadas para antídoto del factor Xa

Country Status (14)

Country	Link
US (6)	US20160237420A1 (2)
EP (2)	EP3750556A1 (2)
JP (4)	JP6742986B2 (2)
KR (3)	KR102867491B1 (2)
CN (2)	CN113171447B (2)
AU (3)	AU2015305413B2 (2)
CA (1)	CA2961739C (2)
DK (1)	DK3182993T3 (2)
EA (2)	EA036091B1 (2)
ES (1)	ES2814157T3 (2)
IL (2)	IL250413B (2)
SG (1)	SG11201701247RA (2)
WO (1)	WO2016029061A1 (2)
ZA (1)	ZA201701764B (2)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP3121271B1 (en) *	2009-03-30	2019-07-24	Portola Pharmaceuticals, Inc.	Antidotes for factor xa inhibitors and methods of using the same
EP3750556A1 (en) *	2014-08-20	2020-12-16	Portola Pharmaceuticals, Inc.	Lyophilized formulations for factor xa antidote
WO2017147522A1 (en) *	2016-02-24	2017-08-31	Portola Pharmaceuticals, Inc.	Lyophilized formulations for factor xa antidote
PT3472314T (pt) *	2016-06-17	2021-06-18	Alexion Pharma Inc	Preparação de derivados do fator xa
WO2018213151A1 (en) *	2017-05-18	2018-11-22	Merck Sharp & Dohme Corp.	Pharmaceutical formulation comprising incretin-insulin conjugates
CN112512480B (zh) *	2018-05-21	2024-10-01	中外制药株式会社	被封入玻璃容器的冷冻干燥制剂
CN110760479A (zh) *	2019-05-17	2020-02-07	上海交通大学医学院附属瑞金医院	靶向血小板表达的凝血因子Xa及其应用

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
JPH08504769A (ja)	1992-12-15	1996-05-21	コルバス・インターナショナル、インコーポレイテッド	因子Ｘａの新規インヒビター
DK1820516T3 (da) *	1999-02-22	2013-10-28	Univ Connecticut	Nye albuminfrie faktor VIII-præparater
US6586574B1 (en) *	1999-08-17	2003-07-01	Nn A/S	Stabilization of freeze-dried cake
WO2001064642A2 (en)	2000-02-29	2001-09-07	Cor Therapeutics, Inc.	Benzamides and related inhibitors of factor xa
US6586584B2 (en) *	2001-01-29	2003-07-01	Becton, Dickinson And Company	Sequences and methods for detection of Hepatitis C virus
CA2512680A1 (en) *	2003-01-08	2004-07-29	Chiron Corporation	Stabilized lyophilized compositions comprising tissue factor pathway inhibitor or tissue factor pathway inhibitor variants
PE20070717A1 (es)	2005-11-08	2007-08-17	Millennium Pharm Inc	Sal de maleato y polimorfo de [2-({4-[(dimetilamino)iminometil]fenil}carbonilamino)-5-metoxifenil]-n-(5-cloro-(2-piridil))carboxamida
US9283260B2 (en) *	2006-04-21	2016-03-15	Amgen Inc.	Lyophilized therapeutic peptibody formulations
EP2915564B1 (en) *	2007-09-28	2020-11-04	Portola Pharmaceuticals, Inc.	Antidotes for factor XA inhibitors and methods of using the same
WO2010026186A1 (en)	2008-09-03	2010-03-11	Octapharma Ag	New protecting compositions for recombinantly produced factor viii
MX2011004907A (es) *	2008-11-14	2011-07-29	Portola Pharm Inc	Antidotos para inhibidores del factor xa y metodos para el uso de los mismos en combinacion con agentes de coagulacion de sangre.
EP3121271B1 (en)	2009-03-30	2019-07-24	Portola Pharmaceuticals, Inc.	Antidotes for factor xa inhibitors and methods of using the same
ES2605801T3 (es) *	2009-07-15	2017-03-16	Portola Pharmaceuticals, Inc.	Formulación de dosis unitaria de antídoto para inhibidores del factor Xa para su uso en la prevención de la hemorragia
EP2458990B1 (en) *	2009-07-28	2016-03-30	Merck Sharp & Dohme Corp.	Methods for producing high concentration lyophilized pharmaceutical formulations
US20130165459A1 (en) *	2010-01-12	2013-06-27	Norvartis Pharma Ag	Pharmaceutical composition and dosage forms of elinogrel and methods of use thereof
CA2796729C (en) *	2010-04-20	2020-06-23	Octapharma Ag	Melezitose for stabilizing human blood plasma proteins
JP2013544271A (ja) *	2010-12-03	2013-12-12	ポートラファーマシューティカルズ，インコーポレイテッド	式（ｉ）の化合物の薬学的組成物、投薬形態、および新規の形態、ならびにその使用方法
US9683020B2 (en) *	2011-08-01	2017-06-20	Emory University	VLPS containing ligands and methods related thereto
US9371522B2 (en) *	2011-09-30	2016-06-21	The Children's Hospital Of Philadelphia	Compositions and methods for modulating hemostasis
GB201310946D0 (en) *	2013-06-19	2013-07-31	Cambridge Entpr Ltd	Antidote
EP3750556A1 (en) *	2014-08-20	2020-12-16	Portola Pharmaceuticals, Inc.	Lyophilized formulations for factor xa antidote

2015
- 2015-08-20 EP EP20170763.5A patent/EP3750556A1/en active Pending
- 2015-08-20 KR KR1020227045749A patent/KR102867491B1/ko active Active
- 2015-08-20 KR KR1020177007503A patent/KR102482517B1/ko active Active
- 2015-08-20 EP EP15834421.8A patent/EP3182993B1/en active Active
- 2015-08-20 DK DK15834421.8T patent/DK3182993T3/da active
- 2015-08-20 ES ES15834421T patent/ES2814157T3/es active Active
- 2015-08-20 KR KR1020257032508A patent/KR20250150675A/ko active Pending
- 2015-08-20 SG SG11201701247RA patent/SG11201701247RA/en unknown
- 2015-08-20 CN CN202110363277.0A patent/CN113171447B/zh active Active
- 2015-08-20 JP JP2017509739A patent/JP6742986B2/ja active Active
- 2015-08-20 WO PCT/US2015/046173 patent/WO2016029061A1/en not_active Ceased
- 2015-08-20 CN CN201580048166.3A patent/CN107073082B/zh active Active
- 2015-08-20 EA EA201790415A patent/EA036091B1/ru unknown
- 2015-08-20 EA EA202091385A patent/EA202091385A3/ru unknown
- 2015-08-20 CA CA2961739A patent/CA2961739C/en active Active
- 2015-08-20 AU AU2015305413A patent/AU2015305413B2/en active Active
2016
- 2016-04-22 US US15/136,810 patent/US20160237420A1/en not_active Abandoned
2017
- 2017-02-02 IL IL250413A patent/IL250413B/en active IP Right Grant
- 2017-03-10 ZA ZA2017/01764A patent/ZA201701764B/en unknown
- 2017-11-21 US US15/820,265 patent/US20180320160A1/en not_active Abandoned
2019
- 2019-09-12 JP JP2019165981A patent/JP2019206595A/ja not_active Withdrawn
2020
- 2020-06-08 US US16/895,443 patent/US20200299667A1/en not_active Abandoned
- 2020-06-08 US US16/895,448 patent/US11028382B2/en active Active
- 2020-08-26 IL IL276960A patent/IL276960B/en unknown
- 2020-12-16 AU AU2020289768A patent/AU2020289768B2/en active Active
2021
- 2021-05-28 US US17/334,427 patent/US20210284986A1/en not_active Abandoned
- 2021-10-22 JP JP2021172975A patent/JP7416549B2/ja active Active
2023
- 2023-09-11 JP JP2023146769A patent/JP2023158199A/ja active Pending
2024
- 2024-09-13 AU AU2024219698A patent/AU2024219698A1/en active Pending
- 2024-11-05 US US18/937,646 patent/US20250163399A1/en active Pending

Also Published As

Publication number	Publication date
AU2015305413B2 (en)	2020-09-24
KR102867491B1 (ko)	2025-10-01
JP6742986B2 (ja)	2020-08-19
JP2017525704A (ja)	2017-09-07
KR102482517B1 (ko)	2022-12-28
US20180320160A1 (en)	2018-11-08
KR20250150675A (ko)	2025-10-20
DK3182993T3 (da)	2020-09-21
JP2023158199A (ja)	2023-10-26
CN107073082A (zh)	2017-08-18
US20200299668A1 (en)	2020-09-24
AU2020289768B2 (en)	2024-06-13
IL250413B (en)	2020-09-30
US20210284986A1 (en)	2021-09-16
EP3750556A1 (en)	2020-12-16
KR20230007550A (ko)	2023-01-12
JP7416549B2 (ja)	2024-01-17
CN107073082B (zh)	2021-04-30
WO2016029061A1 (en)	2016-02-25
EA202091385A3 (ru)	2021-06-30
KR20170042776A (ko)	2017-04-19
AU2020289768A1 (en)	2021-01-21
JP2019206595A (ja)	2019-12-05
EA202091385A2 (ru)	2021-03-31
CN113171447B (zh)	2024-05-17
IL276960A (en)	2020-10-29
CA2961739C (en)	2024-04-30
IL276960B (en)	2022-04-01
EA036091B1 (ru)	2020-09-25
CA2961739A1 (en)	2016-02-25
IL250413A0 (en)	2017-03-30
AU2015305413A1 (en)	2017-03-23
ZA201701764B (en)	2020-10-28
SG11201701247RA (en)	2017-03-30
JP2022003101A (ja)	2022-01-11
AU2024219698A1 (en)	2024-10-03
US20160237420A1 (en)	2016-08-18
EP3182993A4 (en)	2018-01-17
EP3182993A1 (en)	2017-06-28
US11028382B2 (en)	2021-06-08
CN113171447A (zh)	2021-07-27
EP3182993B1 (en)	2020-07-01
EA201790415A1 (ru)	2017-08-31
US20200299667A1 (en)	2020-09-24
US20250163399A1 (en)	2025-05-22

Publication	Publication Date	Title
ES2814157T3 (es)	2021-03-26	Formulaciones liofilizadas para antídoto del factor Xa
US12005144B2 (en)	2024-06-11	Lyophilized formulations for factor XA antidote
HK40042818A (en)	2021-09-03	Lyophilized formulations for factor xa antidote
EA048314B1 (ru)	2024-11-19	Лиофилизированные составы для антидота фактора ха
US20130131089A1 (en)	2013-05-23	Dosage forms of elinogrel and methods of injectable administration thereof
WO2011137459A1 (en)	2011-11-03	Dosage forms of elinogrel and methods of injectable administration thereof
HK40001910B (en)	2022-03-11	Lyophilized formulations for factor xa antidote