CA2892104C - Treatment for pulmonary hypertension - Google Patents
Treatment for pulmonary hypertension Download PDFInfo
- Publication number
- CA2892104C CA2892104C CA2892104A CA2892104A CA2892104C CA 2892104 C CA2892104 C CA 2892104C CA 2892104 A CA2892104 A CA 2892104A CA 2892104 A CA2892104 A CA 2892104A CA 2892104 C CA2892104 C CA 2892104C
- Authority
- CA
- Canada
- Prior art keywords
- therapeutic agent
- pulmonary hypertension
- treprostinil
- oral
- inhaled
- 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.)
- Active
Links
- 208000002815 pulmonary hypertension Diseases 0.000 title claims abstract description 28
- 238000011282 treatment Methods 0.000 title claims description 17
- 239000003814 drug Substances 0.000 claims abstract description 45
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 35
- 238000001990 intravenous administration Methods 0.000 claims abstract description 21
- 230000000694 effects Effects 0.000 claims abstract description 18
- 238000007920 subcutaneous administration Methods 0.000 claims abstract description 5
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical group 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 description 66
- 229960005032 treprostinil Drugs 0.000 claims description 48
- 238000001802 infusion Methods 0.000 claims description 19
- 238000002560 therapeutic procedure Methods 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 12
- 229960002890 beraprost Drugs 0.000 claims description 9
- CTPOHARTNNSRSR-APJZLKAGSA-N beraprost Chemical group O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC(O)=O CTPOHARTNNSRSR-APJZLKAGSA-N 0.000 claims description 9
- 230000009885 systemic effect Effects 0.000 claims description 5
- 208000001953 Hypotension Diseases 0.000 claims description 4
- 206010033425 Pain in extremity Diseases 0.000 claims description 4
- 208000007536 Thrombosis Diseases 0.000 claims description 4
- 230000036543 hypotension Effects 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 159000000000 sodium salts Chemical group 0.000 claims description 3
- 230000000977 initiatory effect Effects 0.000 claims description 2
- 230000001934 delay Effects 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 12
- 238000000034 method Methods 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- 238000011260 co-administration Methods 0.000 abstract description 4
- 238000009097 single-agent therapy Methods 0.000 abstract description 4
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 37
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 33
- 229960001123 epoprostenol Drugs 0.000 description 29
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 24
- 241001465754 Metazoa Species 0.000 description 22
- 229940014025 tyvaso Drugs 0.000 description 18
- 238000002648 combination therapy Methods 0.000 description 15
- 229960003065 bosentan Drugs 0.000 description 14
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 description 14
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 12
- HIFJCPQKFCZDDL-ACWOEMLNSA-N iloprost Chemical compound C1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CC#CC)[C@H](O)C[C@@H]21 HIFJCPQKFCZDDL-ACWOEMLNSA-N 0.000 description 12
- 229960003310 sildenafil Drugs 0.000 description 12
- 229940079593 drug Drugs 0.000 description 9
- 238000003305 oral gavage Methods 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 8
- 229960002240 iloprost Drugs 0.000 description 7
- 210000004072 lung Anatomy 0.000 description 7
- 210000001147 pulmonary artery Anatomy 0.000 description 7
- IQKAWAUTOKVMLE-ZSESPEEFSA-M treprostinil sodium Chemical compound [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 7
- 238000013459 approach Methods 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 229940118867 remodulin Drugs 0.000 description 6
- 230000002459 sustained effect Effects 0.000 description 6
- 229940124447 delivery agent Drugs 0.000 description 5
- 231100000824 inhalation exposure Toxicity 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 229960000835 tadalafil Drugs 0.000 description 5
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 5
- 229940105295 ventavis Drugs 0.000 description 5
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 210000003038 endothelium Anatomy 0.000 description 4
- 238000003304 gavage Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 150000003815 prostacyclins Chemical class 0.000 description 4
- 229940127293 prostanoid Drugs 0.000 description 4
- 150000003814 prostanoids Chemical class 0.000 description 4
- 210000005166 vasculature Anatomy 0.000 description 4
- RHWRWEUCEXUUAV-ZSESPEEFSA-N 2-[[(1r,2r,3as,9as)-2-hydroxy-1-[(3s)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalen-5-yl]oxy]acetic acid;2-(2-hydroxyethylamino)ethanol Chemical compound OCCNCCO.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 RHWRWEUCEXUUAV-ZSESPEEFSA-N 0.000 description 3
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 3
- 101000862089 Clarkia lewisii Glucose-6-phosphate isomerase, cytosolic 1A Proteins 0.000 description 3
- 102000002045 Endothelin Human genes 0.000 description 3
- 108050009340 Endothelin Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 230000004087 circulation Effects 0.000 description 3
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 230000002685 pulmonary effect Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 230000024883 vasodilation Effects 0.000 description 3
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 230000003466 anti-cipated effect Effects 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229950000586 aviptadil Drugs 0.000 description 2
- 108010006060 aviptadil Proteins 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical group OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 230000003292 diminished effect Effects 0.000 description 2
- 239000002308 endothelin receptor antagonist Substances 0.000 description 2
- 210000003989 endothelium vascular Anatomy 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000006995 pathophysiological pathway Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001839 systemic circulation Effects 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- KXYGKDBONOVZOM-UHFFFAOYSA-N 1h-cyclopenta[a]naphthalene Chemical class C1=CC=CC2=C3CC=CC3=CC=C21 KXYGKDBONOVZOM-UHFFFAOYSA-N 0.000 description 1
- 206010048554 Endothelial dysfunction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000009079 Epoprostenol Receptors Human genes 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 102400001263 NT-proBNP Human genes 0.000 description 1
- 101800001904 NT-proBNP Proteins 0.000 description 1
- 108091006335 Prostaglandin I receptors Proteins 0.000 description 1
- 101000604905 Rattus norvegicus Phenylalanine-4-hydroxylase Proteins 0.000 description 1
- 206010039163 Right ventricular failure Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 description 1
- 229960002414 ambrisentan Drugs 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- -1 beraprost Chemical compound 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 208000037815 bloodstream infection Diseases 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000002542 deteriorative effect Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 150000002066 eicosanoids Chemical class 0.000 description 1
- 230000008694 endothelial dysfunction Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 229940041682 inhalant solution Drugs 0.000 description 1
- 238000002664 inhalation therapy Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000013383 initial experiment Methods 0.000 description 1
- 238000013101 initial test Methods 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- JGCMEBMXRHSZKX-UHFFFAOYSA-N macitentan Chemical compound C=1C=C(Br)C=CC=1C=1C(NS(=O)(=O)NCCC)=NC=NC=1OCCOC1=NC=C(Br)C=N1 JGCMEBMXRHSZKX-UHFFFAOYSA-N 0.000 description 1
- 229960001039 macitentan Drugs 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 231100000279 safety data Toxicity 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 210000001321 subclavian vein Anatomy 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 239000003767 thromboxane receptor stimulating agent Substances 0.000 description 1
- 229960001726 treprostinil sodium Drugs 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
- A61K31/5585—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pulmonology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Otolaryngology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Urology & Nephrology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28265910P | 2010-03-15 | 2010-03-15 | |
| US61/282,659 | 2010-03-15 | ||
| CA2791081A CA2791081C (en) | 2010-03-15 | 2011-03-14 | Treatment for pulmonary hypertension |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2791081A Division CA2791081C (en) | 2010-03-15 | 2011-03-14 | Treatment for pulmonary hypertension |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2892104A1 CA2892104A1 (en) | 2011-09-22 |
| CA2892104C true CA2892104C (en) | 2016-08-30 |
Family
ID=43858371
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2892104A Active CA2892104C (en) | 2010-03-15 | 2011-03-14 | Treatment for pulmonary hypertension |
| CA2791081A Active CA2791081C (en) | 2010-03-15 | 2011-03-14 | Treatment for pulmonary hypertension |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2791081A Active CA2791081C (en) | 2010-03-15 | 2011-03-14 | Treatment for pulmonary hypertension |
Country Status (8)
| Country | Link |
|---|---|
| US (2) | US8609728B2 (OSRAM) |
| EP (2) | EP3108888B1 (OSRAM) |
| JP (4) | JP5681276B2 (OSRAM) |
| KR (3) | KR101508047B1 (OSRAM) |
| CN (1) | CN102883722B (OSRAM) |
| CA (2) | CA2892104C (OSRAM) |
| ES (2) | ES2790859T3 (OSRAM) |
| WO (1) | WO2011115922A1 (OSRAM) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2252570B1 (en) | 2007-12-17 | 2017-04-05 | United Therapeutics Corporation | An improved process to prepare treprostinil, the active ingredient in remodulin ® |
| CN102883722B (zh) | 2010-03-15 | 2014-11-05 | 联合治疗公司 | 用于肺动脉高血压的治疗 |
| EP2576492B1 (en) | 2010-06-03 | 2017-09-20 | United Therapeutics Corporation | Treprostinil production |
| JP5580491B2 (ja) | 2011-03-02 | 2014-08-27 | ユナイテッド セラピューティクス コーポレイション | トレプロスチニル製造のための中間体の合成 |
| US9387214B2 (en) | 2012-01-13 | 2016-07-12 | United Therapeutics Corporation | Method of identifying therapies for pulmonary hypertension |
| CA3212313A1 (en) | 2013-03-14 | 2014-10-02 | United Therapeutics Corporation | Solid forms of treprostinil |
| CN109608326A (zh) | 2013-03-15 | 2019-04-12 | 联合治疗公司 | 曲前列环素的盐 |
| CA2908244C (en) | 2013-03-25 | 2021-04-20 | United Therapeutics Corporation | Process of making prostacyclin compounds with linker thiol and pegylated forms |
| BR112016009207B1 (pt) | 2013-10-25 | 2022-11-22 | Insmed Incorporated | Compostos de prostaciclina |
| WO2015089105A1 (en) | 2013-12-09 | 2015-06-18 | Respira Therapeutics, Inc. | Pde5 inhibitor powder formulations and methods relating thereto |
| JP2017517550A (ja) | 2014-06-13 | 2017-06-29 | ユナイテッド セラピューティクス コーポレイション | トレプロスチニル製剤 |
| EP3209415B1 (en) | 2014-10-20 | 2020-02-19 | United Therapeutics Corporation | Synthesis of intermediates for producing prostacyclin derivatives |
| CA2967385C (en) | 2014-11-18 | 2023-05-16 | Insmed Incorporated | Methods of manufacturing treprostinil and treprostinil derivative prodrugs |
| RU2748278C2 (ru) | 2016-07-15 | 2021-05-21 | Акселерон Фарма Инк. | Композиции и способы лечения легочной гипертензии |
| EP3515430A1 (en) | 2016-09-26 | 2019-07-31 | United Therapeutics Corporation | Treprostinil prodrugs |
| CN110381951A (zh) | 2016-12-14 | 2019-10-25 | 瑞必治公司 | 用于治疗肺性高血压和其他肺病症的方法及组合物 |
| KR20190030805A (ko) * | 2017-09-14 | 2019-03-25 | 경상대학교산학협력단 | 폐고혈압 예방 또는 치료용 흡입제, 및 이의 투여방법 |
| HU231296B1 (hu) * | 2018-03-09 | 2022-09-28 | Chinoin Zrt | Eljárás treprostinil-dietanol-amin só B polimorf formájának előállítására |
| ES2976468T3 (es) | 2018-09-18 | 2024-08-01 | Lilly Co Eli | Sal de treprostinil erbumina |
| KR20220002600A (ko) | 2019-04-29 | 2022-01-06 | 인스메드 인코포레이티드 | 트레프로스티닐 전구약물의 건조 분말 조성물 및 이의 사용 방법 |
| CN113811307A (zh) | 2019-05-14 | 2021-12-17 | 国邑药品科技股份有限公司 | 弱酸药物的医药组合物及给药方法 |
| CA3149358A1 (en) | 2019-08-23 | 2021-03-04 | United Therapeutics Corporation | Treprostinil prodrugs |
| IL296567A (en) | 2020-04-17 | 2022-11-01 | United Therapeutics Corp | Terfostinil for use in the treatment of interstitial lung disease |
| US11793780B2 (en) | 2020-06-09 | 2023-10-24 | United Therapeutics Corporation | Prodrugs of treprosiinil |
| CN117062605A (zh) | 2020-12-14 | 2023-11-14 | 联合治疗公司 | 使用曲前列环素前药治疗疾病的方法 |
| CA3209987A1 (en) | 2021-03-03 | 2022-09-09 | Hitesh Batra | A dry powder composition of trestinil and its prodrug thereof and further comprising comprising (e)-3,6-bis[4-(n-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (fdkp) |
| US20230263807A1 (en) | 2022-02-08 | 2023-08-24 | United Therapeutics Corporation | Treprostinil iloprost combination therapy |
| JP2025515512A (ja) | 2022-04-29 | 2025-05-15 | 兆科薬業（広州）有限公司 | トレプロスチニルソフトミスト吸入剤 |
| WO2024155752A1 (en) | 2023-01-19 | 2024-07-25 | United Therapeutics Corporation | Treprostinil analogs |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4306075A (en) | 1980-03-28 | 1981-12-15 | The Upjohn Company | Composition and process |
| GB8814438D0 (en) | 1988-06-17 | 1988-07-20 | Wellcome Found | Compounds for use in medicine |
| GB9011588D0 (en) | 1990-05-24 | 1990-07-11 | Wellcome Found | Prostaglandin analogues for use in medicine |
| GB9311920D0 (en) * | 1993-06-09 | 1993-07-28 | Pfizer Ltd | Therapeutic agents |
| EP1045695B1 (en) | 1997-11-14 | 2004-03-24 | United Therapeutics Corporation | Use of 9-deoxy-2', 9-alpha-methano-3- oxa-4,5,6- trinor-3, 7-(1',3'-interphenylene) -13,14-dihydro- prostaglandin f 1? to treat peripheral vascular disease |
| US6521212B1 (en) | 1999-03-18 | 2003-02-18 | United Therapeutics Corporation | Method for treating peripheral vascular disease by administering benzindene prostaglandins by inhalation |
| US6803386B2 (en) | 2002-01-16 | 2004-10-12 | United Therapeutics Corporation | Prostacyclin derivative containing compositions and methods of using the same for the treatment of cancer |
| CA2959852A1 (en) | 2003-05-22 | 2005-01-27 | United Therapeutics Corporation | Compounds and methods for delivery of prostacyclin analogs |
| US8765813B2 (en) | 2003-12-16 | 2014-07-01 | United Therapeutics Corporation | Use of treprostinil to treat and prevent ischemic lesions |
| DE602004022982D1 (de) | 2003-12-16 | 2009-10-15 | United Therapeutics Corp | Verwendung von treprostinil zur verbesserung der nierenfunktion |
| WO2005099680A2 (en) | 2004-04-12 | 2005-10-27 | United Therapeutics, Inc. | Use of treprostinil to treat neuropathic diabetic foot ulcers |
| KR101390579B1 (ko) | 2006-05-15 | 2014-05-19 | 유나이티드 세러퓨틱스 코오포레이션 | 정량 흡입기를 사용한 트레프로스티닐 투여 |
| US20090036465A1 (en) | 2006-10-18 | 2009-02-05 | United Therapeutics Corporation | Combination therapy for pulmonary arterial hypertension |
| CN102648916A (zh) | 2007-02-09 | 2012-08-29 | 联合治疗公司 | 用于间质性肺病和哮喘的曲前列尼治疗 |
| KR101693049B1 (ko) | 2007-09-07 | 2017-01-04 | 유나이티드 세러퓨틱스 코오포레이션 | 그람 음성 박테리아에 대한 선택적인 살균 활성을 갖는 완충 용액 및 이의 이용방법 |
| KR20110010753A (ko) | 2008-05-08 | 2011-02-07 | 유나이티드 세러퓨틱스 코오포레이션 | 트레프로스티닐 일수화물 |
| EP2330893A4 (en) | 2008-09-25 | 2013-01-09 | Aradigm Corp | DEEP PULMONARY ADMINISTRATION OF TREPROSTINIL |
| KR101544246B1 (ko) | 2009-05-07 | 2015-08-12 | 유나이티드 세러퓨틱스 코오포레이션 | 프로스타시클린 유사체의 고체 제제 |
| CN102883722B (zh) | 2010-03-15 | 2014-11-05 | 联合治疗公司 | 用于肺动脉高血压的治疗 |
| US20120010159A1 (en) | 2010-07-09 | 2012-01-12 | United Therapeutics Corporation | Combination therapies with cox-2 inhibitors and treprostinil |
-
2011
- 2011-03-14 CN CN201180023177.8A patent/CN102883722B/zh active Active
- 2011-03-14 EP EP16182514.6A patent/EP3108888B1/en active Active
- 2011-03-14 ES ES16182514T patent/ES2790859T3/es active Active
- 2011-03-14 KR KR1020127026242A patent/KR101508047B1/ko active Active
- 2011-03-14 CA CA2892104A patent/CA2892104C/en active Active
- 2011-03-14 CA CA2791081A patent/CA2791081C/en active Active
- 2011-03-14 KR KR1020157004406A patent/KR20150027846A/ko not_active Ceased
- 2011-03-14 KR KR1020167031528A patent/KR20160132501A/ko not_active Ceased
- 2011-03-14 WO PCT/US2011/028390 patent/WO2011115922A1/en not_active Ceased
- 2011-03-14 US US13/047,033 patent/US8609728B2/en active Active
- 2011-03-14 JP JP2013500129A patent/JP5681276B2/ja active Active
- 2011-03-14 ES ES11711190.6T patent/ES2611187T3/es active Active
- 2011-03-14 EP EP11711190.6A patent/EP2547341B1/en active Active
-
2013
- 2013-05-22 US US13/899,734 patent/US8969409B2/en active Active
-
2015
- 2015-01-08 JP JP2015002312A patent/JP2015129129A/ja active Pending
-
2016
- 2016-03-16 JP JP2016052406A patent/JP2016153413A/ja not_active Withdrawn
-
2018
- 2018-05-08 JP JP2018089769A patent/JP2018135383A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ES2611187T3 (es) | 2017-05-05 |
| CN102883722A (zh) | 2013-01-16 |
| US20110224236A1 (en) | 2011-09-15 |
| JP5681276B2 (ja) | 2015-03-04 |
| JP2018135383A (ja) | 2018-08-30 |
| EP2547341A1 (en) | 2013-01-23 |
| CN102883722B (zh) | 2014-11-05 |
| EP3108888A1 (en) | 2016-12-28 |
| ES2790859T3 (es) | 2020-10-29 |
| CA2791081A1 (en) | 2011-09-22 |
| JP2013522303A (ja) | 2013-06-13 |
| KR20130038835A (ko) | 2013-04-18 |
| JP2015129129A (ja) | 2015-07-16 |
| US8969409B2 (en) | 2015-03-03 |
| EP3108888B1 (en) | 2020-02-12 |
| KR101508047B1 (ko) | 2015-04-06 |
| KR20160132501A (ko) | 2016-11-18 |
| KR20150027846A (ko) | 2015-03-12 |
| CA2892104A1 (en) | 2011-09-22 |
| WO2011115922A1 (en) | 2011-09-22 |
| US8609728B2 (en) | 2013-12-17 |
| CA2791081C (en) | 2015-08-25 |
| US20130253049A1 (en) | 2013-09-26 |
| EP2547341B1 (en) | 2016-09-14 |
| JP2016153413A (ja) | 2016-08-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2892104C (en) | Treatment for pulmonary hypertension | |
| US6521212B1 (en) | Method for treating peripheral vascular disease by administering benzindene prostaglandins by inhalation | |
| JP5757677B2 (ja) | 門脈圧亢進症の予防及び／又は治療 | |
| US20070197544A1 (en) | Iloprost in combination therapies for the treatment of pulmonary arterial hypertension | |
| JP2009513660A (ja) | 肺動脈性高血圧の治療用併用療法におけるファスジル | |
| US8324247B2 (en) | Method for treating pulmonary arterial hypertension | |
| US11413273B2 (en) | Prophylactic or therapeutic agent for pulmonary hypertension comprising unsaturated 5-membered heterocycle-containing compound | |
| JP2005060359A (ja) | 血管系病態の治療及び予防のためのジピリダモール、アセチルサリチル酸及びアンギオテンシンｉｉ拮抗薬の使用 | |
| MXPA03007462A (es) | Uso de dipiridamol, acido acetilsalicilico y un antagonista de la angiotensina ii para el tratamiento y la prevencion de eventos vasculares. | |
| Olschewski | From Concept to Therapy–Alternative Route of Drug Application: Inhalation | |
| CA2437709A1 (en) | Use of dipyridamole, acetylsalicylic acid and an angiotensin ii antagonist for treatment and prevention of vascular events | |
| KR20190030805A (ko) | 폐고혈압 예방 또는 치료용 흡입제, 및 이의 투여방법 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20150520 |