JP2020536850A - 虚血を処置するための粘稠性組成物 - Google Patents
虚血を処置するための粘稠性組成物 Download PDFInfo
- Publication number
- JP2020536850A JP2020536850A JP2020512696A JP2020512696A JP2020536850A JP 2020536850 A JP2020536850 A JP 2020536850A JP 2020512696 A JP2020512696 A JP 2020512696A JP 2020512696 A JP2020512696 A JP 2020512696A JP 2020536850 A JP2020536850 A JP 2020536850A
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- hyaluronan
- kda
- viscosity
- molecular weight
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title abstract description 29
- 208000028867 ischemia Diseases 0.000 title description 31
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 82
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-MNSSHETKSA-N 0.000 claims abstract description 78
- 229940099552 hyaluronan Drugs 0.000 claims abstract description 77
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 69
- 230000000302 ischemic effect Effects 0.000 claims abstract description 24
- 239000003527 fibrinolytic agent Substances 0.000 claims abstract description 14
- 239000011159 matrix material Substances 0.000 claims abstract description 13
- 239000000306 component Substances 0.000 claims abstract description 11
- 239000008358 core component Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 28
- 210000001519 tissue Anatomy 0.000 claims description 27
- 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 claims description 26
- 229960005080 warfarin Drugs 0.000 claims description 26
- 206010012601 diabetes mellitus Diseases 0.000 claims description 25
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 claims description 18
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 18
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 18
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 claims description 12
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 claims description 12
- 229960000187 tissue plasminogen activator Drugs 0.000 claims description 11
- 108010023197 Streptokinase Proteins 0.000 claims description 9
- 230000002491 angiogenic effect Effects 0.000 claims description 9
- 229960005202 streptokinase Drugs 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 229960000103 thrombolytic agent Drugs 0.000 claims description 7
- -1 retabase Chemical compound 0.000 claims description 6
- 108010058207 Anistreplase Proteins 0.000 claims description 5
- 210000003205 muscle Anatomy 0.000 claims description 5
- 108010035532 Collagen Proteins 0.000 claims description 4
- 102000008186 Collagen Human genes 0.000 claims description 4
- 108010073385 Fibrin Proteins 0.000 claims description 4
- 102000009123 Fibrin Human genes 0.000 claims description 4
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 claims description 4
- 208000025865 Ulcer Diseases 0.000 claims description 4
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 claims description 4
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 claims description 4
- 229920001436 collagen Polymers 0.000 claims description 4
- 229950003499 fibrin Drugs 0.000 claims description 4
- 229940094857 kinlytic Drugs 0.000 claims description 4
- 229920001282 polysaccharide Polymers 0.000 claims description 4
- 231100000397 ulcer Toxicity 0.000 claims description 4
- 229960005356 urokinase Drugs 0.000 claims description 4
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 claims description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 claims description 3
- 239000012190 activator Substances 0.000 claims description 3
- 210000002744 extracellular matrix Anatomy 0.000 claims description 3
- 150000004676 glycans Chemical class 0.000 claims description 3
- 229940012957 plasmin Drugs 0.000 claims description 3
- 239000005017 polysaccharide Substances 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- 108090000623 proteins and genes Proteins 0.000 claims description 3
- NMHIUKCEPXGTRP-HCWXCVPCSA-N streptose Chemical compound C[C@H](O)[C@](O)(C=O)[C@@H](O)C=O NMHIUKCEPXGTRP-HCWXCVPCSA-N 0.000 claims 2
- 238000010586 diagram Methods 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 50
- 210000003141 lower extremity Anatomy 0.000 description 45
- 230000017531 blood circulation Effects 0.000 description 34
- 238000001356 surgical procedure Methods 0.000 description 22
- 230000037396 body weight Effects 0.000 description 21
- 238000011282 treatment Methods 0.000 description 13
- 210000004204 blood vessel Anatomy 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 9
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 9
- 229960005001 ticlopidine Drugs 0.000 description 9
- 210000003414 extremity Anatomy 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 7
- 206010017711 Gangrene Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000033115 angiogenesis Effects 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 4
- 229960003160 hyaluronic acid Drugs 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 206010028851 Necrosis Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000003511 endothelial effect Effects 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 210000001105 femoral artery Anatomy 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 230000002980 postoperative effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000003954 umbilical cord Anatomy 0.000 description 3
- 101100387368 Arabidopsis thaliana DIT2-1 gene Proteins 0.000 description 2
- 239000004971 Cross linker Substances 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 101150025279 DIT1 gene Proteins 0.000 description 2
- 101150085690 DIT2 gene Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102000013566 Plasminogen Human genes 0.000 description 2
- 108010051456 Plasminogen Proteins 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 108010039185 Tenecteplase Proteins 0.000 description 2
- 239000003994 anesthetic gas Substances 0.000 description 2
- 210000003423 ankle Anatomy 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- KXCLCNHUUKTANI-RBIYJLQWSA-N keratan Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@H](COS(O)(=O)=O)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@H](O[C@@H](O[C@H]3[C@H]([C@@H](COS(O)(=O)=O)O[C@@H](O)[C@@H]3O)O)[C@H](NC(C)=O)[C@H]2O)COS(O)(=O)=O)O[C@H](COS(O)(=O)=O)[C@@H]1O KXCLCNHUUKTANI-RBIYJLQWSA-N 0.000 description 2
- 201000002818 limb ischemia Diseases 0.000 description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 2
- 210000004623 platelet-rich plasma Anatomy 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 108010073863 saruplase Proteins 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 210000003371 toe Anatomy 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 description 1
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 101100115215 Caenorhabditis elegans cul-2 gene Proteins 0.000 description 1
- 101100171060 Caenorhabditis elegans div-1 gene Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 229920002567 Chondroitin Polymers 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 229920000045 Dermatan sulfate Polymers 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 108010041308 Endothelial Growth Factors Proteins 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- AZKVWQKMDGGDSV-BCMRRPTOSA-N Genipin Chemical compound COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12 AZKVWQKMDGGDSV-BCMRRPTOSA-N 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 229920002971 Heparan sulfate Polymers 0.000 description 1
- 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 1
- 241000282412 Homo Species 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 229920000288 Keratan sulfate Polymers 0.000 description 1
- 102000007547 Laminin Human genes 0.000 description 1
- 108010085895 Laminin Proteins 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000029549 Muscle injury Diseases 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 206010053648 Vascular occlusion Diseases 0.000 description 1
- 102100035140 Vitronectin Human genes 0.000 description 1
- 108010031318 Vitronectin Proteins 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 229940099983 activase Drugs 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000002870 angiogenesis inducing agent Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 229960000983 anistreplase Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 230000009693 chronic damage Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- AVJBPWGFOQAPRH-FWMKGIEWSA-L dermatan sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@H](OS([O-])(=O)=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](C([O-])=O)O1 AVJBPWGFOQAPRH-FWMKGIEWSA-L 0.000 description 1
- 229940051593 dermatan sulfate Drugs 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 150000002016 disaccharides Chemical group 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical class C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 238000010230 functional analysis Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012213 gelatinous substance Substances 0.000 description 1
- AZKVWQKMDGGDSV-UHFFFAOYSA-N genipin Natural products COC(=O)C1=COC(O)C2C(CO)=CCC12 AZKVWQKMDGGDSV-UHFFFAOYSA-N 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 208000014617 hemorrhoid Diseases 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229940014041 hyaluronate Drugs 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 1
- 229960004752 ketorolac Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000009681 mesenchymal cell proliferation Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 238000009832 plasma treatment Methods 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 108010051412 reteplase Proteins 0.000 description 1
- 229960002917 reteplase Drugs 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960000216 tenecteplase Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 229940113038 tnkase Drugs 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 208000021331 vascular occlusion disease Diseases 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K38/18—Growth factors; Growth regulators
- A61K38/1858—Platelet-derived growth factor [PDGF]
- A61K38/1866—Vascular endothelial growth factor [VEGF]
-
- 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
-
- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K9/0012—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
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/56—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 without hydrogen atoms in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Vascular Medicine (AREA)
- Dermatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Inorganic Chemistry (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Polymers & Plastics (AREA)
- Materials Engineering (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
本出願は、内容が本明細書中参照により組み込まれている、2017年9月1日に出願の米国特許仮出願番号第62/553,269号に対する優先権を主張する。
よって、本明細書において、虚血性組織を処置するための医薬組成物を記載する。本組成物は、血栓溶解薬を含むコア成分とヒアルロナンまたはその誘導体を含むマトリックス成分とを含む。本医薬組成物は、10mPa・s超の粘度を有する。粘度の測定に関して選択されるパラメータ(たとえばスピンドルおよび回転速度)に応じて、本組成物の粘度は、10〜10000mPa・s(たとえば10〜100、50〜150、100〜200、150〜250、250〜500、500〜1000、1000〜1500、1500〜2000、2000〜2500、2500〜3000、3000〜3500、3500〜5000、5000〜6000、6000〜7000、7000〜8000、8000〜9000、または9000〜10000)の範囲にあり得る。
本医薬組成物の有効量が、虚血性処置するために患者に投与され得る。これは、虚血性組織(たとえば筋肉)に直接または当該組織の近くに投与(たとえば注射または塗布)され得る。本組成物は、粘稠度(consistency)においてゼラチン性また粘稠性であり、静脈内投与されない。
雄性のC57BL/6マウスを、国立成功大学(National Cheng Kung University:NCKU)の研究動物センターまたはBioLASCO Taiwan Co., Ltdから調達した。これらマウスは、実験を行う前に環境に適応させるため、少なくとも1週間、NCKUのバイオテクノロジー研究所の動物施設に収容した。行われた全ての実験は、NCKUでIACUC(Institutional Animal Care and Use Committee)によりあらかじめ承認されたものであった。
様々な分子量であり異なる濃度のヒアルロナンを含む複数の組成物を生成した。
5mg/ml、平均分子量1560kDaのヒアルロナンと、VEGFとを含む組成物(DIV)を、マウスに投与し、その下肢および血流に及ぼす効果を、上記の実施例1に記載のように評価した。外科手術後にこの組成物で処置されなかった糖尿病マウスは、対照として使用した。VEGF医薬は、文献において血管新生作用を有することが記載されている。ヒトにおけるVEGFの最大有効量および最小有効量を、体重によってマウスの用量に変換した。
1000〜1800kDaの範囲の分子量を有する5mg/mlのヒアルロナンと、チクロピジンとを含む組成物(DIT)をマウスに投与し、その下肢および血流に及ぼす効果を、上記の実施例1に記載されるように評価した。外科手術後にこの組成物で処置しなかった糖尿病マウスは、対照として使用した。ヒトのチクロピジンの最大有効量および最小有効量を、体重によってマウスの用量に変換した。
5mg/ml、平均分子量1,560kDaのヒアルロナンとワルファリンとを含む組成物(DIW)をマウスに投与し、その下肢および血流に及ぼす効果を、上記の実施例1に記載されるように評価した。外科手術後にこの組成物で処置しなかった糖尿病マウスは、対照として使用した。ヒトのワルファリンの最大有効量および最小有効量を、体重によってマウスの用量に変換した。
DWI2グループおよび対照グループのマウスを、さらに機能について評価した。この評価は、手術後35日目に行った。
下肢虚血を有する糖尿病マウスを、実施例1に記載のように作製した。このマウスを、ワルファリンと、5mg/ml、分子量の範囲が1000〜1800kDaのヒアルロナンとを含む組成物で、上記に記載のDIW2グループのマウスと同様に70ng/g体重のワルファリンの用量ではあるが、手術後異なる時点で処置した。図9に示すように、手術後に処置が遅れた場合、下肢の外観スコアは、遅れた長さに応じて減少したことが観察された。にもかかわらず、処置が、手術後48時間程度遅れて行われた場合であっても、外観スコアは手術後28日目で未だ約9ポイントであり、足指の壊死のみを伴い肢の一部が残ったことを表した。処置が72時間遅れた場合、下肢の壊死を回復させることはできなかった。
本医薬組成物において異なる分子量のヒアルロナンが治療効果に影響を及ぼすかどうかを研究した。
粘度が本医薬組成物の治療効果に影響するかどうかを調査した。
本明細書で開示される全ての特性は、任意の組み合わせで組み合わせることができる。本明細書で開示される各特性は、同じ目的、同等の目的、または同様の目的を供給する別の特性によって置き換えられ得る。よって、特段他が記載されない限り、開示される各特性は、同等または類似の特性の全般的なシリーズの単なる例である。
Claims (32)
- 虚血性組織を処置するための医薬組成物であって、
血栓溶解薬を含むコア成分とヒアルロナンまたはその誘導体を含むマトリックス成分とを含み、前記医薬組成物が10mPa・s超の粘度を有する、
医薬組成物。 - 前記粘度が、10〜10000mPa・sである、請求項1に記載の医薬組成物。
- 前記ヒアルロナンが、100kDa〜5000kDaの平均分子量を有する、請求項2に記載の医薬組成物。
- 前記ヒアルロナンが、700kDa〜2000kDaの平均分子量を有する、請求項3に記載の医薬組成物。
- 1mg/ml〜100mg/mlの前記ヒアルロナンを含む、請求項3に記載の医薬組成物。
- 前記粘度が、700〜2000kDaの平均分子量を有する3〜10mg/mlの前記ヒアルロナンの粘度の範囲内にある、請求項1に記載の医薬組成物。
- 前記粘度が、1560kDaの平均分子量を有する5mg/mlの前記ヒアルロナンの粘度と同じである、請求項1に記載の医薬組成物。
- 前記ヒアルロナンの平均分子量が、700〜2000kDaであり、前記ヒアルロナンの濃度が、3〜10mg/mlである、請求項6に記載の医薬組成物。
- 前記ヒアルロナンの平均分子量が、1560kDaであり、前記ヒアルロナンの濃度が、5mg/mlである、請求項7に記載の医薬組成物。
- 前記マトリックス成分がさらに、コラーゲン、細胞外マトリックス因子、タンパク質、または多糖を含む、請求項1に記載の医薬組成物。
- 前記血栓溶解薬が、チクロピジン、ワルファリン、組織プラスミノーゲンアクチベーター、エミナーゼ(eminase)、レタバーゼ(retavase)、ストレプターゼ(streptase)、組織プラスミノーゲンアクチベーター、テネクテプラーゼ、アボキナーゼ、kinlytic、ウロキナーゼ、プロウロキナーゼ、アニソイル化された精製ストレプトキナーゼ活性化複合体(anisoylated purified streptokinase activator complex:APSAC)、フィブリン、およびプラスミンからなる群から選択される、請求項1〜10のいずれか1項に記載の医薬組成物。
- 血管新生化合物をさらに含む、請求項1〜11のいずれか1項に記載の医薬組成物。
- 前記血管新生化合物が、血管内皮増殖因子(VEGF)である、請求項12に記載の医薬組成物。
- 前記虚血性組織に直接投与されるが、静脈内に投与されない、請求項1〜13のいずれか1項に記載の医薬組成物。
- 前記虚血性組織が、対象の潰瘍であるか、または対象の心臓もしくは肢にある、請求項14に記載の医薬組成物。
- 前記虚血性組織が、筋肉である、請求項15に記載の医薬組成物。
- 対象の虚血性組織を処置する方法であって、前記虚血性組織に直接医薬組成物を投与するステップを含み、ただし前記医薬組成物は静脈内投与されず、
前記医薬組成物が、血栓溶解薬を含むコア成分とヒアルロナンまたはその誘導体を含むマトリックス成分とを含み、前記医薬組成物が10mPa・s超の粘度を有する、
方法。 - 前記虚血性組織が、対象の潰瘍であるか、または対象の心臓もしくは肢にある、請求項17に記載の方法。
- 前記虚血性組織が、筋肉である、請求項18に記載の方法。
- 前記対象が、糖尿病を有する、請求項17に記載の方法。
- 前記粘度が、10〜10000mPa・sである、請求項17〜20のいずれか1項に記載の方法。
- 前記ヒアルロナンが、100kDa〜5000kDaの平均分子量を有する、請求項21に記載の方法。
- 前記ヒアルロナンが、700kDa〜2000kDaの平均分子量を有する、請求項22に記載の方法。
- 前記医薬組成物が、1mg/ml〜100mg/mlの前記ヒアルロナンを含む、請求項21に記載の方法。
- 前記粘度が、700〜2000kDaの平均分子量を有する3〜10mg/mlの前記ヒアルロナンの粘度の範囲内にある、請求項21に記載の方法。
- 前記粘度が、1560kDaの平均分子量を有する5mg/mlの前記ヒアルロナンの粘度と同じである、請求項21に記載の方法。
- 前記ヒアルロナンの平均分子量が、700〜2000kDaであり、前記ヒアルロナンの濃度が、3〜10mg/mlである、請求項25に記載の方法。
- 前記ヒアルロナンの平均分子量が、1560kDaであり、前記ヒアルロナンの濃度が、5mg/mlである、請求項26に記載の方法。
- 前記マトリックス成分がさらに、コラーゲン、細胞外マトリックス因子、タンパク質、または多糖を含む、請求項17〜28のいずれか1項に記載の方法。
- 前記血栓溶解薬が、チクロピジン、ワルファリン、組織プラスミノーゲンアクチベーター、エミナーゼ(eminase)、レタバーゼ(retavase)、ストレプターゼ(streptase)、組織プラスミノーゲンアクチベーター、テネクテプラーゼ、アボキナーゼ、kinlytic、ウロキナーゼ、プロウロキナーゼ、アニソイル化された精製ストレプトキナーゼ活性化複合体(anisoylated purified streptokinase activator complex:APSAC)、フィブリン、およびプラスミンからなる群から選択される、請求項17〜28のいずれか1項に記載の方法。
- 血管新生化合物をさらに含む、請求項17〜28のいずれか1項に記載の方法。
- 前記血管新生化合物が、血管内皮増殖因子(VEGF)である、請求項31に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762553269P | 2017-09-01 | 2017-09-01 | |
US62/553,269 | 2017-09-01 | ||
PCT/US2018/049003 WO2019046670A1 (en) | 2017-09-01 | 2018-08-31 | VISCOUS COMPOSITION FOR THE TREATMENT OF ISCHEMIA |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2020536850A true JP2020536850A (ja) | 2020-12-17 |
JP2020536850A5 JP2020536850A5 (ja) | 2021-10-07 |
Family
ID=65525032
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020512696A Pending JP2020536850A (ja) | 2017-09-01 | 2018-08-31 | 虚血を処置するための粘稠性組成物 |
Country Status (9)
Country | Link |
---|---|
US (1) | US20210069297A1 (ja) |
EP (1) | EP3675862A4 (ja) |
JP (1) | JP2020536850A (ja) |
KR (1) | KR20200083973A (ja) |
CN (2) | CN116999555A (ja) |
AU (1) | AU2018324111B2 (ja) |
CA (1) | CA3074442A1 (ja) |
TW (2) | TWI775934B (ja) |
WO (1) | WO2019046670A1 (ja) |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH05186362A (ja) * | 1991-07-10 | 1993-07-27 | Takeda Chem Ind Ltd | 水溶性組成物 |
WO1996005845A2 (en) * | 1994-02-23 | 1996-02-29 | Hyal Pharmaceutical Corporation | Treatment of disease and conditions associated with macrophage infiltration in particular stroke and myocardial infarction |
US20070149617A1 (en) * | 2005-11-14 | 2007-06-28 | Deckelbaum Richard J | Use of an omega-3 lipid-based emulsion following ischemic injury to provide protection and recovery in human organs |
JP2012012395A (ja) * | 2010-07-05 | 2012-01-19 | Alain Villette | 注射薬と粘稠成分でなる注射薬組成物 |
JP2012125180A (ja) * | 2010-12-15 | 2012-07-05 | Kowa Co | 下肢虚血モデル動物 |
JP2013539761A (ja) * | 2010-10-07 | 2013-10-28 | ナショナル チェン クン ユニバーシティー | 血管新生の促進のためのヒアルロナンの使用 |
US20140287004A1 (en) * | 2005-11-14 | 2014-09-25 | The Trustees Of Columbia University In The City Of New York | Use of an Omega-3 Lipid-Based Emulsion Following Ischemic Injury to Provide Protection and Recovery in Human Organs |
KR20150030682A (ko) * | 2015-02-04 | 2015-03-20 | (주)웰빙해피팜 | 항염증과 항혈액응고 성분들을 함유한 히알루론산(ha) 유착 억제 생체 소재 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5820879A (en) * | 1993-02-12 | 1998-10-13 | Access Pharmaceuticals, Inc. | Method of delivering a lipid-coated condensed-phase microparticle composition |
AU5624500A (en) * | 1999-06-18 | 2001-01-09 | Collaborative Group, Ltd., The | Hyaluronic acid microspheres for sustained gene transfer |
CA2494316A1 (en) * | 2002-08-06 | 2004-02-12 | Genvec, Inc. | Improved injection system |
CN105311057A (zh) * | 2014-07-29 | 2016-02-10 | 黄玲惠 | 含胶原蛋白与透明质酸的细胞组织胶体 |
-
2018
- 2018-08-31 AU AU2018324111A patent/AU2018324111B2/en active Active
- 2018-08-31 KR KR1020207009329A patent/KR20200083973A/ko not_active Application Discontinuation
- 2018-08-31 US US16/642,273 patent/US20210069297A1/en active Pending
- 2018-08-31 CA CA3074442A patent/CA3074442A1/en active Pending
- 2018-08-31 CN CN202310977564.XA patent/CN116999555A/zh active Pending
- 2018-08-31 EP EP18849721.8A patent/EP3675862A4/en active Pending
- 2018-08-31 JP JP2020512696A patent/JP2020536850A/ja active Pending
- 2018-08-31 WO PCT/US2018/049003 patent/WO2019046670A1/en unknown
- 2018-08-31 CN CN201880056509.4A patent/CN111182902A/zh active Pending
- 2018-09-03 TW TW107130876A patent/TWI775934B/zh active
- 2018-09-03 TW TW111126542A patent/TW202241407A/zh unknown
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH05186362A (ja) * | 1991-07-10 | 1993-07-27 | Takeda Chem Ind Ltd | 水溶性組成物 |
WO1996005845A2 (en) * | 1994-02-23 | 1996-02-29 | Hyal Pharmaceutical Corporation | Treatment of disease and conditions associated with macrophage infiltration in particular stroke and myocardial infarction |
US20070149617A1 (en) * | 2005-11-14 | 2007-06-28 | Deckelbaum Richard J | Use of an omega-3 lipid-based emulsion following ischemic injury to provide protection and recovery in human organs |
US20140287004A1 (en) * | 2005-11-14 | 2014-09-25 | The Trustees Of Columbia University In The City Of New York | Use of an Omega-3 Lipid-Based Emulsion Following Ischemic Injury to Provide Protection and Recovery in Human Organs |
JP2012012395A (ja) * | 2010-07-05 | 2012-01-19 | Alain Villette | 注射薬と粘稠成分でなる注射薬組成物 |
JP2013539761A (ja) * | 2010-10-07 | 2013-10-28 | ナショナル チェン クン ユニバーシティー | 血管新生の促進のためのヒアルロナンの使用 |
JP2012125180A (ja) * | 2010-12-15 | 2012-07-05 | Kowa Co | 下肢虚血モデル動物 |
KR20150030682A (ko) * | 2015-02-04 | 2015-03-20 | (주)웰빙해피팜 | 항염증과 항혈액응고 성분들을 함유한 히알루론산(ha) 유착 억제 생체 소재 |
Also Published As
Publication number | Publication date |
---|---|
TW201924674A (zh) | 2019-07-01 |
TWI775934B (zh) | 2022-09-01 |
KR20200083973A (ko) | 2020-07-09 |
TW202241407A (zh) | 2022-11-01 |
US20210069297A1 (en) | 2021-03-11 |
AU2018324111B2 (en) | 2023-11-09 |
CA3074442A1 (en) | 2019-03-07 |
AU2018324111A1 (en) | 2020-04-09 |
EP3675862A4 (en) | 2021-06-09 |
CN111182902A (zh) | 2020-05-19 |
WO2019046670A1 (en) | 2019-03-07 |
CN116999555A (zh) | 2023-11-07 |
EP3675862A1 (en) | 2020-07-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11992580B2 (en) | Method of soft tissue augmentation | |
CN108125980A (zh) | 用于稳定的多糖制剂的组合物和方法 | |
RU2674478C2 (ru) | Гиалуроновая кислота и ее применение в лечении венозной недостаточности и варикозного расширения вен | |
KR20110127746A (ko) | 주사용 바이오물질 | |
US9795630B2 (en) | Compositions and methods for inducing or enhancing connective tissue repair | |
EP2624842B1 (en) | Use of hyaluronan for promoting angiogenesis | |
AU2018324111B2 (en) | Viscous composition for treating ischemia | |
JP7333919B2 (ja) | 虚血を治療するためのヘパリン組成物 | |
JP6826657B2 (ja) | 腱変性の処置に使用するための組成物 | |
Lee et al. | Subcutaneous toxicity of a dual ionically cross-linked atelocollagen and sodium hyaluronate gel: Rat in vivo study for biological safety evaluation of the injectable hydrogel | |
Devi et al. | Significance of hyaluronic acid in the biomedical field: A review | |
RU2357735C1 (ru) | Способ лечения критической ишемии нижних конечностей | |
MLF et al. | Clinical evaluation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20201028 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210826 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210826 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220823 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221118 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230110 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230509 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20230510 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20230608 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20230707 |