JP5681276B2 - 肺高血圧症のための治療 - Google Patents
肺高血圧症のための治療 Download PDFInfo
- Publication number
- JP5681276B2 JP5681276B2 JP2013500129A JP2013500129A JP5681276B2 JP 5681276 B2 JP5681276 B2 JP 5681276B2 JP 2013500129 A JP2013500129 A JP 2013500129A JP 2013500129 A JP2013500129 A JP 2013500129A JP 5681276 B2 JP5681276 B2 JP 5681276B2
- Authority
- JP
- Japan
- Prior art keywords
- inhalation
- treprostinil
- oral
- therapeutic agent
- combination
- 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 description 27
- 238000011282 treatment Methods 0.000 title claims description 11
- 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 73
- 239000003814 drug Substances 0.000 claims description 53
- 229960005032 treprostinil Drugs 0.000 claims description 52
- 229940124597 therapeutic agent Drugs 0.000 claims description 32
- 238000001990 intravenous administration Methods 0.000 claims description 22
- 238000002560 therapeutic procedure Methods 0.000 claims description 19
- 150000002148 esters Chemical class 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 238000007920 subcutaneous administration Methods 0.000 claims description 11
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical group OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 3
- 230000001934 delay Effects 0.000 claims description 2
- 230000000977 initiatory effect Effects 0.000 claims description 2
- 159000000000 sodium salts Chemical group 0.000 claims 1
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 38
- 229960001123 epoprostenol Drugs 0.000 description 33
- 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 26
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 25
- 238000001802 infusion Methods 0.000 description 25
- 241001465754 Metazoa Species 0.000 description 21
- 229940014025 tyvaso Drugs 0.000 description 21
- 230000000694 effects Effects 0.000 description 20
- 238000000034 method Methods 0.000 description 18
- 238000002648 combination therapy Methods 0.000 description 17
- 229960003065 bosentan Drugs 0.000 description 15
- 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 15
- 229960003310 sildenafil Drugs 0.000 description 13
- 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
- 229940079593 drug Drugs 0.000 description 11
- IQKAWAUTOKVMLE-ZSESPEEFSA-M treprostinil sodium Chemical group [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 11
- 230000008901 benefit Effects 0.000 description 10
- 238000003305 oral gavage Methods 0.000 description 10
- 230000007423 decrease Effects 0.000 description 9
- 229940118867 remodulin Drugs 0.000 description 9
- LMHIPJMTZHDKEW-XQYLJSSYSA-M Epoprostenol sodium Chemical compound [Na+].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 LMHIPJMTZHDKEW-XQYLJSSYSA-M 0.000 description 8
- 229960002890 beraprost Drugs 0.000 description 8
- CTPOHARTNNSRSR-APJZLKAGSA-N beraprost Chemical compound 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 description 8
- 229960002240 iloprost Drugs 0.000 description 7
- 230000007774 longterm Effects 0.000 description 7
- 210000001147 pulmonary artery Anatomy 0.000 description 7
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000002459 sustained effect Effects 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 5
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 5
- 208000007536 Thrombosis Diseases 0.000 description 5
- 229940124447 delivery agent Drugs 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 230000002685 pulmonary effect Effects 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
- 208000001953 Hypotension Diseases 0.000 description 4
- 206010022086 Injection site pain Diseases 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 230000036543 hypotension Effects 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 231100000824 inhalation exposure Toxicity 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
- 239000000126 substance Substances 0.000 description 4
- 230000009885 systemic effect Effects 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
- 102000002045 Endothelin Human genes 0.000 description 3
- 108050009340 Endothelin Proteins 0.000 description 3
- 206010033425 Pain in extremity Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000011260 co-administration Methods 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
- 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
- 210000003038 endothelium Anatomy 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000002664 inhalation therapy Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000006995 pathophysiological pathway Effects 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 238000009097 single-agent therapy Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 206010048554 Endothelial dysfunction Diseases 0.000 description 2
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000008694 endothelial dysfunction Effects 0.000 description 2
- 239000002308 endothelin receptor antagonist Substances 0.000 description 2
- 210000003989 endothelium vascular Anatomy 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 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
- 238000012261 overproduction Methods 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001839 systemic circulation Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 239000003767 thromboxane receptor stimulating agent Substances 0.000 description 2
- 230000000304 vasodilatating effect Effects 0.000 description 2
- 230000024883 vasodilation 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 compound C1=CC=CC2=C3CC=CC3=CC=C21 KXYGKDBONOVZOM-UHFFFAOYSA-N 0.000 description 1
- 102000010180 Endothelin receptor Human genes 0.000 description 1
- 108050001739 Endothelin receptor Proteins 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
- 102100026476 Prostacyclin receptor Human genes 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
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000001464 adherent effect Effects 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
- 230000037147 athletic performance Effects 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 229950000586 aviptadil Drugs 0.000 description 1
- 108010006060 aviptadil Proteins 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect 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
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 150000002066 eicosanoids Chemical class 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000003966 growth inhibitor Substances 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
- 239000003112 inhibitor Substances 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
- 238000010253 intravenous injection Methods 0.000 description 1
- 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 1
- 230000000622 irritating effect Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 230000002147 killing effect Effects 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
- 238000007726 management method Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002688 persistence 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
- 150000003174 prostaglandin I2 derivatives Chemical class 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000004088 pulmonary circulation Effects 0.000 description 1
- 238000011552 rat model Methods 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
- 210000002345 respiratory system Anatomy 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
- 229960001726 treprostinil sodium Drugs 0.000 description 1
- 230000006444 vascular growth Effects 0.000 description 1
- 230000006442 vascular tone Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 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)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Nutrition Science (AREA)
- Otolaryngology (AREA)
- Physiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (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 | ||
| PCT/US2011/028390 WO2011115922A1 (en) | 2010-03-15 | 2011-03-14 | Treatment for pulmonary hypertension |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2015002312A Division JP2015129129A (ja) | 2010-03-15 | 2015-01-08 | 肺高血圧症のための治療 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2013522303A JP2013522303A (ja) | 2013-06-13 |
| JP2013522303A5 JP2013522303A5 (enExample) | 2014-05-01 |
| JP5681276B2 true JP5681276B2 (ja) | 2015-03-04 |
Family
ID=43858371
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2013500129A Active JP5681276B2 (ja) | 2010-03-15 | 2011-03-14 | 肺高血圧症のための治療 |
| JP2015002312A Pending JP2015129129A (ja) | 2010-03-15 | 2015-01-08 | 肺高血圧症のための治療 |
| JP2016052406A Withdrawn JP2016153413A (ja) | 2010-03-15 | 2016-03-16 | 肺高血圧症のための治療 |
| JP2018089769A Pending JP2018135383A (ja) | 2010-03-15 | 2018-05-08 | 肺高血圧症のための治療 |
Family Applications After (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2015002312A Pending JP2015129129A (ja) | 2010-03-15 | 2015-01-08 | 肺高血圧症のための治療 |
| JP2016052406A Withdrawn JP2016153413A (ja) | 2010-03-15 | 2016-03-16 | 肺高血圧症のための治療 |
| JP2018089769A Pending JP2018135383A (ja) | 2010-03-15 | 2018-05-08 | 肺高血圧症のための治療 |
Country Status (8)
| Country | Link |
|---|---|
| US (2) | US8609728B2 (enExample) |
| EP (2) | EP3108888B1 (enExample) |
| JP (4) | JP5681276B2 (enExample) |
| KR (3) | KR20160132501A (enExample) |
| CN (1) | CN102883722B (enExample) |
| CA (2) | CA2892104C (enExample) |
| ES (2) | ES2790859T3 (enExample) |
| WO (1) | WO2011115922A1 (enExample) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103274926B (zh) | 2007-12-17 | 2016-08-10 | 联合治疗公司 | 一种制备Remodulin中的活性成分曲前列素的改良方法 |
| KR20160132501A (ko) | 2010-03-15 | 2016-11-18 | 유나이티드 세러퓨틱스 코오포레이션 | 폐고혈압의 치료 |
| KR101868166B1 (ko) | 2010-06-03 | 2018-06-15 | 유나이티드 세러퓨틱스 코오포레이션 | 트레프로스티닐의 제조 |
| 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 |
| CA2904598C (en) | 2013-03-15 | 2021-10-05 | United Therapeutics Corporation | Salts of treprostinil |
| CN105228451B (zh) | 2013-03-25 | 2018-03-30 | 联合治疗公司 | 制备具有硫醇连接子和聚乙二醇化形式的前列环素化合物的方法 |
| US20170049739A1 (en) | 2013-10-25 | 2017-02-23 | Insmed Incorporated | Prostacyclin compounds, compositions and methods of use thereof |
| WO2015089105A1 (en) | 2013-12-09 | 2015-06-18 | Respira Therapeutics, Inc. | Pde5 inhibitor powder formulations and methods relating thereto |
| WO2015192030A1 (en) | 2014-06-13 | 2015-12-17 | United Therapeutics Corporation | Treprostinil formulations |
| ES2778274T3 (es) | 2014-10-20 | 2020-08-10 | United Therapeutics Corp | Síntesis de productos intermedios para producir derivados de prostaciclina |
| JP6866043B2 (ja) | 2014-11-18 | 2021-04-28 | インスメッド インコーポレイテッド | トレプロスチニルプロドラッグおよびトレプロスチニル誘導体プロドラッグの製造方法 |
| RS62011B1 (sr) | 2016-07-15 | 2021-07-30 | Acceleron Pharma Inc | Kompozicije koje sadrže polipeptide actriia za upotrebu u lečenju plućne hipertenzije |
| CN110678174A (zh) | 2016-09-26 | 2020-01-10 | 联合治疗学有限公司 | 曲前列环素的前药 |
| CA3046025A1 (en) * | 2016-12-14 | 2018-06-21 | Respira Therapeutics, Inc. | Methods and compositions for treatment of pulmonary hypertension and other lung disorders |
| 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 |
| CN112739679B (zh) | 2018-09-18 | 2024-03-12 | 伊莱利利公司 | 曲前列环素的特丁胺盐 |
| MX2021013329A (es) | 2019-04-29 | 2022-03-17 | Insmed Inc | Composiciones de polvo seco de los profarmacos de treprostinil y métodos de uso de las mismas. |
| US12064406B2 (en) * | 2019-05-14 | 2024-08-20 | Pharmosa Biopharm Inc. | Pharmaceutical composition of a weak acid drug and methods of administration |
| JP2022546314A (ja) | 2019-08-23 | 2022-11-04 | ユナイテッド セラピューティクス コーポレイション | トレプロスチニルプロドラッグ |
| EP4135707A1 (en) | 2020-04-17 | 2023-02-22 | United Therapeutics Corporation | Treprostinil for use in the treatment of intersitial lung disease |
| CN116113415A (zh) | 2020-06-09 | 2023-05-12 | 联合治疗公司 | 曲前列尼尔的富马酰基二酮哌啶前药 |
| JP2023553989A (ja) | 2020-12-14 | 2023-12-26 | ユナイテッド セラピューティクス コーポレイション | トレプロスチニルプロドラッグで疾患を治療する方法 |
| KR20240012354A (ko) | 2021-03-03 | 2024-01-29 | 유나이티드 쎄러퓨틱스 코포레이션 | (e)-3,6-비스[4-(n-카보닐-2-프로페닐)아미도부틸]-2,5-디케토피페라진(fdkp)을 추가로 포함하는, 트레프로스티닐 및 이의 프로드러그의 건조 분말 조성물 |
| AU2023219692A1 (en) | 2022-02-08 | 2024-08-01 | United Therapeutics Corporation | Treprostinil iloprost combination therapy |
| US20250288597A1 (en) | 2022-04-29 | 2025-09-18 | Zhaoke Pharmaceutical (Guangzhou) Co., Ltd | Treprostinil soft mist inhalant |
| CN121241041A (zh) | 2023-01-19 | 2025-12-30 | 联合治疗公司 | 曲前列尼尔类似物及相关制备和使用方法 |
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 |
| GB9301192D0 (en) * | 1993-06-09 | 1993-06-09 | Trott Francis W | Flower shaped mechanised table |
| KR100638684B1 (ko) | 1997-11-14 | 2006-10-27 | 유나이티드 세러퓨틱스 코오포레이션 | 말초 혈관 질환의 치료를 위한 9-데옥시-2',9-알파-메타노-3-옥사-4,5,6-트리노르-3,7-(1',3'-인터페닐렌)-13,14-디하이드로-프로스타글란딘 에프1의 용도 |
| 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 |
| EP1628654B2 (en) | 2003-05-22 | 2019-12-04 | United Therapeutics Corporation | Compounds and methods for delivery of prostacyclin analogs |
| ATE441418T1 (de) | 2003-12-16 | 2009-09-15 | United Therapeutics Corp | Verwendung von treprostinil zur verbesserung der nierenfunktion |
| ATE473736T1 (de) | 2003-12-16 | 2010-07-15 | United Therapeutics Corp | Verwendung von treprostinil zur behandlung von ischämischen läsionen |
| ATE462427T1 (de) | 2004-04-12 | 2010-04-15 | United Therapeutics Corp | Verwendung von treprostinil zur behandlung von neuropathischen diabetischen fussgeschwüren |
| WO2007134292A2 (en) | 2006-05-15 | 2007-11-22 | United Therapeutics Corporation | Treprostinil administration using a metered dose inhaler |
| US20090036465A1 (en) | 2006-10-18 | 2009-02-05 | United Therapeutics Corporation | Combination therapy for pulmonary arterial hypertension |
| JP2010518122A (ja) * | 2007-02-09 | 2010-05-27 | ユナイテッド セラピューティクス コーポレーション | 間質性肺疾患および喘息のためのトレプロスチニル処置 |
| CN103181893A (zh) | 2007-09-07 | 2013-07-03 | 联合治疗公司 | 针对革兰氏阴性细菌具有选择性杀菌活性的缓冲液及其使用方法 |
| KR20110010753A (ko) | 2008-05-08 | 2011-02-07 | 유나이티드 세러퓨틱스 코오포레이션 | 트레프로스티닐 일수화물 |
| CN102164487A (zh) | 2008-09-25 | 2011-08-24 | 阿拉迪姆公司 | 曲前列素的深肺部递送 |
| WO2010129757A1 (en) | 2009-05-07 | 2010-11-11 | United Therapeutics Corporation | Solid formulations of prostacyclin analogs |
| KR20160132501A (ko) | 2010-03-15 | 2016-11-18 | 유나이티드 세러퓨틱스 코오포레이션 | 폐고혈압의 치료 |
| WO2012006273A1 (en) | 2010-07-09 | 2012-01-12 | United Therapeutics Corporation | Combination therapies with cox-2 inhibitors and treprostinil |
-
2011
- 2011-03-14 KR KR1020167031528A patent/KR20160132501A/ko not_active Ceased
- 2011-03-14 US US13/047,033 patent/US8609728B2/en active Active
- 2011-03-14 CA CA2892104A patent/CA2892104C/en active Active
- 2011-03-14 CN CN201180023177.8A patent/CN102883722B/zh active Active
- 2011-03-14 WO PCT/US2011/028390 patent/WO2011115922A1/en not_active Ceased
- 2011-03-14 CA CA2791081A patent/CA2791081C/en active Active
- 2011-03-14 ES ES16182514T patent/ES2790859T3/es active Active
- 2011-03-14 ES ES11711190.6T patent/ES2611187T3/es active Active
- 2011-03-14 KR KR1020127026242A patent/KR101508047B1/ko active Active
- 2011-03-14 JP JP2013500129A patent/JP5681276B2/ja active Active
- 2011-03-14 KR KR1020157004406A patent/KR20150027846A/ko not_active Ceased
- 2011-03-14 EP EP16182514.6A patent/EP3108888B1/en 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 |
|---|---|
| KR20130038835A (ko) | 2013-04-18 |
| KR20160132501A (ko) | 2016-11-18 |
| EP2547341A1 (en) | 2013-01-23 |
| CA2892104C (en) | 2016-08-30 |
| CA2791081C (en) | 2015-08-25 |
| JP2015129129A (ja) | 2015-07-16 |
| US8609728B2 (en) | 2013-12-17 |
| US20130253049A1 (en) | 2013-09-26 |
| EP3108888A1 (en) | 2016-12-28 |
| JP2018135383A (ja) | 2018-08-30 |
| CN102883722B (zh) | 2014-11-05 |
| US20110224236A1 (en) | 2011-09-15 |
| CA2892104A1 (en) | 2011-09-22 |
| KR101508047B1 (ko) | 2015-04-06 |
| JP2013522303A (ja) | 2013-06-13 |
| JP2016153413A (ja) | 2016-08-25 |
| EP2547341B1 (en) | 2016-09-14 |
| US8969409B2 (en) | 2015-03-03 |
| EP3108888B1 (en) | 2020-02-12 |
| ES2790859T3 (es) | 2020-10-29 |
| WO2011115922A1 (en) | 2011-09-22 |
| KR20150027846A (ko) | 2015-03-12 |
| CA2791081A1 (en) | 2011-09-22 |
| ES2611187T3 (es) | 2017-05-05 |
| CN102883722A (zh) | 2013-01-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5681276B2 (ja) | 肺高血圧症のための治療 | |
| CN1196479C (zh) | 吸入形式的苯并茚前列腺素制剂的用途 | |
| US20220008436A1 (en) | Treprostinil administration by inhalation | |
| US20050101608A1 (en) | Iloprost in combination therapies for the treatment of pulmonary arterial hypertension | |
| US8324247B2 (en) | Method for treating pulmonary arterial hypertension | |
| KR20120138229A (ko) | 정맥내 투여용 이부프로펜을 이용한 중증 환자의 치료 | |
| KR20120089623A (ko) | 정맥내 투여용 이부프로펜을 이용한 환자의 치료 | |
| JP7369523B2 (ja) | 中等度～重度のインフルエンザの処置 | |
| JP6935930B2 (ja) | 生薬成分を含む肺高血圧症の予防又は治療剤 | |
| KR20190030805A (ko) | 폐고혈압 예방 또는 치료용 흡입제, 및 이의 투여방법 | |
| HK1248161A1 (en) | Milrinone composition and method for administering same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140311 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20140311 |
|
| A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20140311 |
|
| A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20140402 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140415 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20140702 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20140709 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20141008 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20141209 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20150108 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 5681276 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |