WO2008008437A1 - Poly(ester-amides), leurs dérivés et leur emploi dans des dispositifs médicaux implantables - Google Patents
Poly(ester-amides), leurs dérivés et leur emploi dans des dispositifs médicaux implantables Download PDFInfo
- Publication number
- WO2008008437A1 WO2008008437A1 PCT/US2007/015902 US2007015902W WO2008008437A1 WO 2008008437 A1 WO2008008437 A1 WO 2008008437A1 US 2007015902 W US2007015902 W US 2007015902W WO 2008008437 A1 WO2008008437 A1 WO 2008008437A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- poly
- amide
- ester
- group
- medical device
- Prior art date
Links
- -1 poly(ester amide Chemical class 0.000 claims abstract description 69
- 229920000642 polymer Polymers 0.000 claims description 126
- 239000003814 drug Substances 0.000 claims description 118
- 229940079593 drug Drugs 0.000 claims description 76
- 125000000217 alkyl group Chemical group 0.000 claims description 64
- 239000000126 substance Substances 0.000 claims description 50
- 229940124597 therapeutic agent Drugs 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 28
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims description 25
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 24
- 239000003431 cross linking reagent Substances 0.000 claims description 23
- 229960005167 everolimus Drugs 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 19
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
- 229920000554 ionomer Polymers 0.000 claims description 16
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 15
- 150000001768 cations Chemical class 0.000 claims description 15
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 229920005569 poly(vinylidene fluoride-co-hexafluoropropylene) Polymers 0.000 claims description 10
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000005442 diisocyanate group Chemical group 0.000 claims description 8
- 229920001244 Poly(D,L-lactide) Polymers 0.000 claims description 7
- 230000009477 glass transition Effects 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 229920001490 poly(butyl methacrylate) polymer Polymers 0.000 claims description 7
- 229920006149 polyester-amide block copolymer Polymers 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 239000007983 Tris buffer Substances 0.000 claims description 4
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims description 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- OVBFMUAFNIIQAL-UHFFFAOYSA-N 1,4-diisocyanatobutane Chemical compound O=C=NCCCCN=C=O OVBFMUAFNIIQAL-UHFFFAOYSA-N 0.000 claims description 3
- DFPJRUKWEPYFJT-UHFFFAOYSA-N 1,5-diisocyanatopentane Chemical compound O=C=NCCCCCN=C=O DFPJRUKWEPYFJT-UHFFFAOYSA-N 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- AYLRODJJLADBOB-QMMMGPOBSA-N methyl (2s)-2,6-diisocyanatohexanoate Chemical compound COC(=O)[C@@H](N=C=O)CCCCN=C=O AYLRODJJLADBOB-QMMMGPOBSA-N 0.000 claims description 3
- 229920001434 poly(D-lactide) Polymers 0.000 claims description 3
- 229920001432 poly(L-lactide) Polymers 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 229910052709 silver Inorganic materials 0.000 claims description 3
- 239000004332 silver Substances 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- XQUPVDVFXZDTLT-UHFFFAOYSA-N 1-[4-[[4-(2,5-dioxopyrrol-1-yl)phenyl]methyl]phenyl]pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C(C=C1)=CC=C1CC1=CC=C(N2C(C=CC2=O)=O)C=C1 XQUPVDVFXZDTLT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 2
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229920003192 poly(bis maleimide) Polymers 0.000 claims description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 2
- 230000035876 healing Effects 0.000 abstract description 17
- 229920001971 elastomer Polymers 0.000 abstract description 2
- 239000011247 coating layer Substances 0.000 abstract 1
- 239000000806 elastomer Substances 0.000 abstract 1
- 239000010410 layer Substances 0.000 description 149
- 239000000463 material Substances 0.000 description 27
- 229920001223 polyethylene glycol Polymers 0.000 description 15
- 238000000576 coating method Methods 0.000 description 14
- 208000037803 restenosis Diseases 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- 239000011248 coating agent Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 229940024606 amino acid Drugs 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 11
- 150000001413 amino acids Chemical class 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 0 C*C=Cc1ccccc1 Chemical compound C*C=Cc1ccccc1 0.000 description 9
- 125000000524 functional group Chemical group 0.000 description 9
- 229920001279 poly(ester amides) Polymers 0.000 description 9
- 208000007536 Thrombosis Diseases 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 230000009286 beneficial effect Effects 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 230000028709 inflammatory response Effects 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 6
- 229920006373 Solef Polymers 0.000 description 6
- 230000036760 body temperature Effects 0.000 description 6
- 238000004132 cross linking Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 6
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical class O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 5
- 229920002988 biodegradable polymer Polymers 0.000 description 5
- 239000004621 biodegradable polymer Substances 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 229920001400 block copolymer Polymers 0.000 description 4
- 230000036755 cellular response Effects 0.000 description 4
- 239000000824 cytostatic agent Substances 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 229920001519 homopolymer Polymers 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 125000003010 ionic group Chemical group 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N lysine Chemical compound NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 229920002959 polymer blend Polymers 0.000 description 4
- 238000006116 polymerization reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 4
- 229960002930 sirolimus Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000036642 wellbeing Effects 0.000 description 4
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 4
- 229950009819 zotarolimus Drugs 0.000 description 4
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- 206010068065 Burning mouth syndrome Diseases 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000004472 Lysine Substances 0.000 description 3
- 210000001367 artery Anatomy 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000007857 degradation product Substances 0.000 description 3
- 229920000295 expanded polytetrafluoroethylene Polymers 0.000 description 3
- 229950003499 fibrin Drugs 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 229960003136 leucine Drugs 0.000 description 3
- 229960003646 lysine Drugs 0.000 description 3
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 3
- 229950004354 phosphorylcholine Drugs 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 229920000058 polyacrylate Polymers 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 229920001059 synthetic polymer Polymers 0.000 description 3
- 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 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- CDMDQYCEEKCBGR-UHFFFAOYSA-N 1,4-diisocyanatocyclohexane Chemical compound O=C=NC1CCC(N=C=O)CC1 CDMDQYCEEKCBGR-UHFFFAOYSA-N 0.000 description 2
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 2
- ZSZRUEAFVQITHH-UHFFFAOYSA-N 2-(2-methylprop-2-enoyloxy)ethyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CC(=C)C(=O)OCCOP([O-])(=O)OCC[N+](C)(C)C ZSZRUEAFVQITHH-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- HXDOZKJGKXYMEW-UHFFFAOYSA-N CCc(cc1)ccc1O Chemical compound CCc(cc1)ccc1O HXDOZKJGKXYMEW-UHFFFAOYSA-N 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 102000016942 Elastin Human genes 0.000 description 2
- 108010014258 Elastin Proteins 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229920002683 Glycosaminoglycan Polymers 0.000 description 2
- 239000004395 L-leucine Substances 0.000 description 2
- 235000019454 L-leucine Nutrition 0.000 description 2
- 206010029113 Neovascularisation Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 102000019197 Superoxide Dismutase Human genes 0.000 description 2
- 108010012715 Superoxide dismutase Proteins 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 206010047163 Vasospasm Diseases 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 239000004019 antithrombin Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 238000010382 chemical cross-linking Methods 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 238000007887 coronary angioplasty Methods 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 229920006037 cross link polymer Polymers 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229920002549 elastin Polymers 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 230000003628 erosive effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 229910001000 nickel titanium Inorganic materials 0.000 description 2
- 239000002840 nitric oxide donor Substances 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920002627 poly(phosphazenes) Polymers 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229940032362 superoxide dismutase Drugs 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- KWPACVJPAFGBEQ-IKGGRYGDSA-N (2s)-1-[(2r)-2-amino-3-phenylpropanoyl]-n-[(3s)-1-chloro-6-(diaminomethylideneamino)-2-oxohexan-3-yl]pyrrolidine-2-carboxamide Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)CCl)C1=CC=CC=C1 KWPACVJPAFGBEQ-IKGGRYGDSA-N 0.000 description 1
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 1
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 description 1
- GQGRDYWMOPRROR-ZIFKCHSBSA-N (e)-7-[(1r,2r,3s,5s)-3-hydroxy-5-[(4-phenylphenyl)methoxy]-2-piperidin-1-ylcyclopentyl]hept-4-enoic acid Chemical compound O([C@H]1C[C@@H]([C@@H]([C@H]1CC\C=C\CCC(O)=O)N1CCCCC1)O)CC(C=C1)=CC=C1C1=CC=CC=C1 GQGRDYWMOPRROR-ZIFKCHSBSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- NPNPZTNLOVBDOC-UHFFFAOYSA-N 1,1-difluoroethane Chemical compound CC(F)F NPNPZTNLOVBDOC-UHFFFAOYSA-N 0.000 description 1
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- GNSFRPWPOGYVLO-UHFFFAOYSA-N 3-hydroxypropyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCCO GNSFRPWPOGYVLO-UHFFFAOYSA-N 0.000 description 1
- YFICSDVNKFLZRQ-UHFFFAOYSA-N 3-trimethylsilylpropyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCC[Si](C)(C)C YFICSDVNKFLZRQ-UHFFFAOYSA-N 0.000 description 1
- XUXUHDYTLNCYQQ-UHFFFAOYSA-N 4-amino-TEMPO Chemical group CC1(C)CC(N)CC(C)(C)N1[O] XUXUHDYTLNCYQQ-UHFFFAOYSA-N 0.000 description 1
- YSFGBPCBPNVLOK-UHFFFAOYSA-N 6-hydroxy-2-methylhex-2-enamide Chemical compound NC(=O)C(C)=CCCCO YSFGBPCBPNVLOK-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010056375 Bile duct obstruction Diseases 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- MMMJKCJKQUNPKF-UHFFFAOYSA-N CC(C)(CC(CC1(C)C)C(OC)=O)N1O Chemical compound CC(C)(CC(CC1(C)C)C(OC)=O)N1O MMMJKCJKQUNPKF-UHFFFAOYSA-N 0.000 description 1
- ADPYSZNUBWNLDH-UHFFFAOYSA-N CC1C=CC(C)CC1 Chemical compound CC1C=CC(C)CC1 ADPYSZNUBWNLDH-UHFFFAOYSA-N 0.000 description 1
- RAZJCAHPZWSISA-UHFFFAOYSA-N CCC(C)c(cccc1)c1NC Chemical compound CCC(C)c(cccc1)c1NC RAZJCAHPZWSISA-UHFFFAOYSA-N 0.000 description 1
- WLGNXHUBDJTPEW-UHFFFAOYSA-N CCCC1=C[IH]C=CN1C Chemical compound CCCC1=C[IH]C=CN1C WLGNXHUBDJTPEW-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000014882 Carotid artery disease Diseases 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 229920001499 Heparinoid Polymers 0.000 description 1
- 108010007267 Hirudins Proteins 0.000 description 1
- 102000007625 Hirudins Human genes 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910000990 Ni alloy Inorganic materials 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000016222 Pancreatic disease Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 229910000566 Platinum-iridium alloy Inorganic materials 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001273 Polyhydroxy acid Polymers 0.000 description 1
- 239000004642 Polyimide Substances 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920002396 Polyurea Polymers 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- GNVMUORYQLCPJZ-UHFFFAOYSA-M Thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 206010046406 Ureteric obstruction Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 206010070693 Vascular dissection Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- WAIPAZQMEIHHTJ-UHFFFAOYSA-N [Cr].[Co] Chemical class [Cr].[Co] WAIPAZQMEIHHTJ-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229920000180 alkyd Polymers 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940003354 angiomax Drugs 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 1
- 229960003856 argatroban Drugs 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- YEESUBCSWGVPCE-UHFFFAOYSA-N azanylidyneoxidanium iron(2+) pentacyanide Chemical compound [Fe++].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.N#[O+] YEESUBCSWGVPCE-UHFFFAOYSA-N 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- OIRCOABEOLEUMC-GEJPAHFPSA-N bivalirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OIRCOABEOLEUMC-GEJPAHFPSA-N 0.000 description 1
- 108010055460 bivalirudin Proteins 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229940045110 chitosan Drugs 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 description 1
- 229960005025 cilazapril Drugs 0.000 description 1
- 208000024980 claudication Diseases 0.000 description 1
- FCSHDIVRCWTZOX-DVTGEIKXSA-N clobetasol Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O FCSHDIVRCWTZOX-DVTGEIKXSA-N 0.000 description 1
- 229960002842 clobetasol Drugs 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- NVIVJPRCKQTWLY-UHFFFAOYSA-N cobalt nickel Chemical compound [Co][Ni][Co] NVIVJPRCKQTWLY-UHFFFAOYSA-N 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 1
- 229960005188 collagen Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- WVIIMZNLDWSIRH-UHFFFAOYSA-N cyclohexylcyclohexane Chemical compound C1CCCCC1C1CCCCC1 WVIIMZNLDWSIRH-UHFFFAOYSA-N 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 210000000188 diaphragm Anatomy 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229910000701 elgiloys (Co-Cr-Ni Alloy) Inorganic materials 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 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 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 239000003822 epoxy resin Substances 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 229960002743 glutamine Drugs 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229920000578 graft copolymer Polymers 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000007773 growth pattern Effects 0.000 description 1
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 239000002554 heparinoid Substances 0.000 description 1
- XXMIOPMDWAUFGU-UHFFFAOYSA-N hexane-1,6-diol Chemical compound OCCCCCCO XXMIOPMDWAUFGU-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940006607 hirudin Drugs 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 108010021336 lanreotide Proteins 0.000 description 1
- 229960002437 lanreotide Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 229940127215 low-molecular weight heparin Drugs 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- HLXZNVUGXRDIFK-UHFFFAOYSA-N nickel titanium Chemical compound [Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni] HLXZNVUGXRDIFK-UHFFFAOYSA-N 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229960002460 nitroprusside Drugs 0.000 description 1
- 231100000065 noncytotoxic Toxicity 0.000 description 1
- 230000002020 noncytotoxic effect Effects 0.000 description 1
- 230000001453 nonthrombogenic effect Effects 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- 229940012843 omega-3 fatty acid Drugs 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical group OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000007888 peripheral angioplasty Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- 125000001639 phenylmethylene group Chemical group [H]C(=*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- HWLDNSXPUQTBOD-UHFFFAOYSA-N platinum-iridium alloy Chemical class [Ir].[Pt] HWLDNSXPUQTBOD-UHFFFAOYSA-N 0.000 description 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 239000005014 poly(hydroxyalkanoate) Substances 0.000 description 1
- 229920000052 poly(p-xylylene) Polymers 0.000 description 1
- 229920001440 poly(ε-caprolactone)-block-poly(ethylene glycol) Polymers 0.000 description 1
- 229920002239 polyacrylonitrile Polymers 0.000 description 1
- 229920001707 polybutylene terephthalate Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000647 polyepoxide Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920000903 polyhydroxyalkanoate Polymers 0.000 description 1
- 229920001721 polyimide Polymers 0.000 description 1
- 239000013047 polymeric layer Substances 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920006216 polyvinyl aromatic Polymers 0.000 description 1
- 229920001290 polyvinyl ester Polymers 0.000 description 1
- 229920001289 polyvinyl ether Polymers 0.000 description 1
- 229920001291 polyvinyl halide Polymers 0.000 description 1
- 229920000131 polyvinylidene Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 229920006214 polyvinylidene halide Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- NMMVKSMGBDRONO-UHFFFAOYSA-N potassium;9-methyl-3-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound [K+].CC1=CC=CN(C2=O)C1=NC=C2C1=NN=N[N-]1 NMMVKSMGBDRONO-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical compound [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- 239000002089 prostaglandin antagonist Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000005070 sphincter Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical compound BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 229950007952 vapiprost Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/44—Polyester-amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- 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
- 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
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/606—Coatings
- A61L2300/608—Coatings having two or more layers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2420/00—Materials or methods for coatings medical devices
- A61L2420/08—Coatings comprising two or more layers
Definitions
- This invention relates to the fields of organic chemistry, polymer chemistry, materials science, and medical devices.
- PTCA percutaneous transluminal coronary angioplasty
- DES drug-eluting stents or DESs were introduced.
- the drugs initially employed with the DES were cytostatic compounds, compounds that curtailed the proliferation of cells that resulted in restenosis. The occurrence of restenosis was thereby reduced to about 5 — 7%, a relatively acceptable figure.
- the DES is the default the industry standard to treatment of atherosclerosis and is rapidly gaining favor for treatment of stenoses of blood vessels other than coronary arteries such as peripheral angioplasty of the femoral artery.
- DESs One of the key criteria of DESs is selection of a polymer or blend of polymers to be used in a drug reservoir layer, a rate-controlling layer, a protective topcoat layer, etc. If a biostable polymer is selected, i.e., a polymer that does not significantly decompose in a patient's body, their chemical composition is often not of significant concern since they are not intended to break down and enter the patient's system. On the other hand, currently biodegradable polymers are preferred for many applications because their ability to decompose in a biological environment confers on them a number of desirable characteristics.
- the fact that a polymer will biodegrade and can eventually be essentially completely eliminated from a patient's body can avoid the need to invasively remove a DES after its job is done.
- biodegradable polymer e.g., selecting one that bio-erodes by bulk erosion or one that bio-erodes by surface erosion, the properties of the polymer can be used as an added tool for the fine-tuning of the release rate of a drug.
- poly(ester-amide)s tend generally to be rather soft and quite permeable to many if not most drugs, which limits their application in DESs to some extent. What is needed is poly(ester-amide)s that are stronger, tougher and less permeable than those currently in use while still maintaining the other beneficial characteristics of the class.
- an implantable medical device that includes a pro-healing influence to counter the delayed healing due to the eluting drugs and therefore to reduce or eliminate the occurrence of late stent thrombosis. While this would be particularly useful with regard to coronary stents, it would also provide substantial benefit to any manner of implantable medical device. For instance, it has been stated that the occurrence of restenosis in the case of lower extremity percutaneous angioplasty is particularly unacceptable (Paul S. Teirstein, Circulation. 2000, 102:2674) and it would be expected that this situation would also be amenable to the effects of stents having pro-healing properties.
- the current invention provides poly(ester-amide)s and methods of their use that address each of the above issues..
- the current invention is directed to poly(ester amide)s and poly(ester amide) derivatives that are stronger, tougher and less permeable than those currently available exhibit and, in addition, that include prohealing characteristics to ameliorate the problem of late stent thrombosis.
- the present invention relates to a poly(ester-amide) having the formula:
- m is an integer from 0 to about 200;
- n is an integer from 0 to about 200;
- k is an integer from 1 to about 3000;
- M n is from about 10,000 to about 1 ,000,000 Da.
- r is a number from 0 to 1 , inclusive;
- s is a number from 0 to 1 , inclusive;
- r + s 1 ;
- X has the chemical structure: R 2
- Y has the chemical structure: wherein:
- R 5 is selected from the group consisting of:
- R 1 and R 4 are independently selected from the group consisting of (1C-12C)alkyl and (2C-12C)alkenyl;
- R 2 , R?. R 2 " and R 2 - are independently selected from the group consisting of hydrogen and (1C-4C)alkyl, wherein: the alkyl group is optionally substituted with a moiety selected from the group consisting of -OH, -SH, -SeH, -C(O)OH, -NHC(NH)NH 2 ,
- R 2 , R 2 -, R 2 - and R 2 - may form a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
- R 3 and R ⁇ are independently selected from the group consisting of (1 C- 12C)alkyl, (2C-12C)alkenyl, (3C-8C)cycloalkyl and -(CH 2 CH 2 ⁇ ) q CH 2 CH2-, wherein q is an integer from 1 to 10, inclusive, wherein the poly(ester-amide) is from about 0.05 mol% to about 5 mol% cross- linked.
- M n is from about 20,000 Da to about 500,000 Da;
- the crosslink is a chemical crosslink.
- the chemical crosslink comprises a reaction product of an -OH, -SH, -NH 2 or -C(O)OH substituent on R 2 , R 2 -, R 2 -, R 2 - or R 6 with a multifunctional OH-reactive, -SH-reactive, -NH 2 - reactive or -C(O)OH- reactive multifunctional crosslinking agent.
- the OH-reactive, -SH-reactive, -NH 2 -reactive or -C(O)OH-reactive multifunctional crosslinking agent comprises a diisocyanate.
- the diisocyanate is selected from the group consisting of 1 ,2-ethanediisocyanate, 1 ,3-propanediisocyanate, 1,4- butanediisocyanate, 1 ,5-pentanediisocyanate, lysine diisocyanate and 1,4- cyclohexanediisocyanate.
- the —SH-reactive multifunctional crosslinking agent comprises a bismaleimide.
- the -OH-reactive, -SH-reactive, NH 2 -reactive or -C(O)OH-reactive multifunctional crosslinking agent comprises a diepoxide.
- the -OH-reactive, -SH-reactive, -NH 2 - reactive or -C(O)OH-reactive multifunctional crosslinking agent comprises a diisothiocyanate.
- the -OH-reactive, -SH-reactive, -NH 2 - reactive or-C(O)OH-reactive multifunctional crosslinking agent comprises a diacid halide.
- R 2 , R 2 -, R 2 - and R 2 - are independently selected from the group consisting of unsubstituted (1C-4C)alkyl and a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
- R 5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CHz) 4 NH-, -(CH 2 ) 4 CH(COR 6 )NH-, -CH(COR 6 )CH(CH 3 )O-,
- R 6 is -OH.
- R 5 is -(CHa) 4 CH(COR 6 )NH-.
- R 2 and R 2 - are -CH 2 CH(CHa) 2 .
- the OH-reactive, SH-reactive, NH 2 reactive, C(O)O H-reactive multifunctional crosslinking agent is a multifunctional aziridine compound.
- the multifunctional aziridine compound is pentaerythriol tris(3-aziridi ⁇ opropionate).
- R 2 , R 2 -, R 2 - and R 2 - are independently selected from the group consisting of unsubstituted (1C-4C)alkyl and a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
- R 5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CH 2 ) 4 NH-, -(CH 2 J 4 CH(COR 6 )NH-, -CH(COR 6 )CH(CH 3 )O-,
- R 6 is -OH.
- R 5 is -(CH 2 J 4 CH(COR 6 )NH-.
- R 2 and R 2 - are -CH 2 CH(CH 3 ) 2 .
- Ri and R 4 are -(CH 2 Je; and, R 3 is -(CH 2 J 6 -.
- R 5 is selected from the group consisting of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CH 2 ) 4 NH-,
- R 6 is selected from the group consisting of -O(1C-20C)alkenyl and -0(CH 2 CH 2 O) C CH 2 CH 2 OR 7 , wherein: q is an integer from 0 to 600, inclusive;
- the chemical crosslink comprises UV or free-radical initiated reaction of the double bond.
- Rs is -(CH 2 J 4 CH(COR 6 )NH-.
- R 6 is selected from
- R 4 are -(CH 2 ) ⁇ -; R 2 and R 2 - are -CH 2 CH(CH 3 ) 2 and R 3 is -(CH 2 J 6 .
- n 0.25.
- Rs is one of R 1 or R 4 is a (2C-12C)alkyenyl, the other is a (1C-12C)alkyl; or, Ri and R 4 are a (2C-12C)alkyenyl and the chemical crosslink comprises UV or free-radical initiated reaction of the alkenyl double bond.
- R 2 and R 2 - are -(CH 2 )CH(CH 3 ) 2 ; and, R 3 is - (CHz) 6 -.
- at least one of R2, Rz, R 2 ". R ? " and R 6 comprises a -C(O)OH group; and the chemical crosslink comprises an ionomer.
- the ionomer comprises a monovalent cation.
- the monovalent cation is selected from the group consisting of sodium, potassium, lithium and silver.
- the ionomer comprises a polyvalent cation.
- the polyvalent cation is selected from the group consisting of calcium(ll), magnesium(ll), zinc(ll), iron(ll) and aluminum(lll).
- R 2 and R 2 ' are independently selected from the group consisting of hydrogen and (1C-4C)alkyl;
- R 5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CH 2 ) 4 NH-, -(CH 2 J 4 CH(COR 6 )NH-, -CH(COR 6 )CH(CH 3 )O-,
- R 6 is -OH.
- R 2 and R 2 - are - CH 2 CH(CH 3 J 2 ; and R 5 is -(CH 2 J 4 CH(COR 6 )NH-.
- Ri and R 4 are - (CH 2 ) 8 -; R 3 is -(CH 2 Je-.
- the ionomer herein comprises Zn(II).
- the cross-link is a physical crosslink.
- A is a soft segment
- B is a hard segment
- the physical crosslink comprises segregated domains of soft segments and paracrystalline hard segments.
- A has a glass-transition temperature of 40 0 C of lower; and, B has a glass transition temperature of 45 0 C or higher.
- R 5 is R 2" R 2-"
- Ri is -(CHaJs-; R2 and R 2 - are -(CH(CH 3 )CH 2 CH 3 ; R 3 is -(CH 2 J 6 -; Rr is -(CH 2 ) 4 -; R 2 - and R 2 - are -CH(CH 3 ) 2 and R 3 - is -(CH 2 ) 3 -.
- Ri is -(CH 2 )4-; R 2 and R 2 - are -(CH(CH 3 )CH 2 CH 3 ; R 3 is -(CH 2 )i 2 -; R 1 . is -(CHz) 4 -; R 2 - and R 2 - are -CH(CH 3 J 2 and R 3 - is -(CH 2 ) 3 -.
- Ri is -(CH 2 ) 8 -;
- R 2 , R 2 -, R 2 - and R 2 - are -(CH(CH 3 )CH 2 CH 3 ;
- R 3 is -(CH 2 ) 6 -;
- R r is -(CH 2 J 2 - and R 3 - is -(CH 2 ) 2 -.
- A is amorphous; B is crystalline; and the crosslink comprises inter-chain crystallization.
- Ri is -(CH 2 )S-; Rr is -(CH 2 ) 4 ; R 2 and R 2 ' are -CH 2 CH(CH 3 ) 2 ; R 2 - and R 2 - are CH 2 phenyl; R 3 is -(CH 2 J 6 -; and, R 3 - is -(CH 2 J 4 -.
- An aspect of this invention is an implantable medical device, comprising: a device body; an optional primer layer; a drug reservoir layer comprising at least one therapeutic agent; an optional rate-controlling layer; and an optional topcoat layer; wherein at least one of the drug reservoir layer, the rate-controlling layer, if opted, and/or the topcoat layer, if opted, comprises a poly (ester-amide) of this invention wherein the poly(ester-amide) has the formula:
- m is an integer from 0 to about 200;
- n is an integer from 0 to about 200;
- k is an integer from 1 to about 3000;
- M w is from about 10,000 to about 1 ,000,000 Da.
- r is a number from 0 to 1 , inclusive;
- s is a number from 0 to 1 , inclusive;
- r + s 1 ;
- Y has the chemical structure: wherein:
- R 5 is selected from the group consisting of:
- Ri and R 4 are independently selected from the group consisting of (1C-12C)alkyl and (2C-12C)alkenyl;
- R 2 , R 2 -, R 2 » and R 2 - are independently selected from the group consisting of hydrogen and (1C-4C)alkyl, wherein: the alkyl group is optionally substituted with a moiety selected from the group consisting of -OH, -SH, -SeH, -C(O)OH, -NHC(NH)NH 2 ,
- phenyl and , or one or more of R 2 , R 2 -, R 2 - and R 2 - may form a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
- F* 3 and Ry are independently selected from the group consisting of (1C-12C)alkyl, (2C-12C)alkenyl, (3C-8C)cycloalkyl and -(CH 2 CH2 ⁇ ) q CH 2 CH 2 -, wherein q is an integer from 1 to 10, inclusive, wherein the poly(ester-amide) is from about 0.05 mol% to about 5 mol% cross- linked.
- M n is from about 20,000 Da to about 500,000 Da.
- the crosslink is a chemical crosslink.
- the chemical crosslink comprises a reaction product of an -OH, -SH, -NH 2 or -C(O)OH substituent on R 2 , Rz, R 2 ", R 2 " or R 6 with a multifunctional OH- reactive, -SH-reactive, -NH 2 - reactive or -C(O)OH-reactive multifunctional crosslinking agent.
- the OH-reactive, -SH-reactive, -NH 2 -reactive or— C(O)OH-reactive multifunctional crosslinking agent comprises a diisocyanate.
- the diisocyanate is selected from the group consisting of 1 ,2-ethanediisocyanate, 1,3- propanediisocyanate, 1 ,4-butanediisocyanate, 1 ,5-pentanediisocyanate, lysine diisocyanate and 1 ,4-cyclohexanediisocyanate.
- R 2 , R 2' , R 2 « and R 2 - are independently selected from the group consisting of unsubstituted (1 C-4C)alkyl and a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
- R 5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CH 2 ) 4 NH-, -(CH 2 J 4 CH(COR 6 )NH-, -CH(COR 6 )CH(CH 3 )O-,
- R 6 is -OH.
- R 5 is -(CH 2 J 4 CH(COR 6 )NH-.
- R 2 and R 2 - are -CH 2 CH(CH 3 ) 2 .
- the OH-reactive, SH-reactive, NH 2 reactive, C(O)OH-reactive multifunctional crosslinking agent is a multifunctional aziridine compound.
- the multifunctional aziridine compound is pentaerythriol tris(3-aziridinopropionate).
- R 2 , R 2 -, R2 " and R 2 - are independently selected from the group consisting of unsubstituted (1C-4C)alkyl and a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
- R 5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CH 2 ) 4 NH-, -(CH 2 J 4 CH(COR 6 )NH-, -CH(COR 6 )CH(CH 3 )O-,
- R 6 is -OH.
- R 5 is -(CH 2 J 4 CH(COR 6 )NH-.
- R 2 and R 2 ' are -CH 2 CH(CH 3 ) 2 .
- Ri and R 4 are -(CH 2 J 8 and R 3 is -(CH 2 )S--
- R 5 is selected from the group consisting of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CH 2 ) 4 N H-,
- R 6 is selected from the group consisting of -O(1C-20C)aIkenyl and -O(CH 2 CH 2 O)qCH 2 CH 2 OR7, wherein: q is an integer from 0 to 600, inclusive;
- the chemical crosslink comprises UV or free-radical initiated reaction of the double bond.
- R 5 is -(CH 2 ⁇ CH(COR 6 )NH-.
- R 6 is selected from the group consisting of
- Ri and R 4 are -(CH 2 ) 8 -; R2 and R 2 - are -CH 2 CH(CH 3 ) 2 and R 3 is -(CH 2 )S-
- R 1 or R 4 is a (2C-12C)alkyenyl, the other is a (1C-12C)alkyl; or,
- Ri and R 4 are a (2C-12C)alkyenyl and the chemical crosslink comprises UV or free-radical initiated reaction of the alkenyl double bond.
- R 2 and R 2 . are -(CH 2 )CH(CHa) 2 ; and, R 3 is -(CH 2 J 6 -.
- At least one of R 2 , R 2 , R 2 -, R 2 - and Re comprises a -C(O)OH group; and the chemical crosslink comprises an ionomer.
- the ionomer comprises a monovalent cation.
- the monovalent cation is selected from the group consisting of sodium, potassium, lithium and silver.
- the ionomer comprises a polyvalent cation.
- the polyvalent cation is selected from the group consisting of calcium(ll), magnesium(ll), zinc(ll), iron(ll) and aluminum(lll).
- R 2 and R. 2 - are independently selected from the group consisting of hydrogen and (1 C-4C)alkyl;
- R 5 is selected from the group consisting of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 XCH 2 )4NH-,
- R 2 and R 2 - are -CH 2 CH(CH 3 ) 2 ; and R 5 is -(CHa) 4 CH(COR 6 )NH-.
- Ri and R4 are -(CH 2 )S-; R3 is -(CH 2 J 6 -.
- the ionomer herein comprises Zn(II).
- the cross-link is a physical crosslink.
- A is a soft segment; B is a hard segment; and, the physical crosslink comprises segregated domains of soft segments and paracrystalline hard segments.
- A has a glass-transition temperature of 40 0 C of lower; and, B has a glass transition temperature of 45 0 C or higher.
- Ri is -(CH 2 )S-; R 2 and R 2 ' are -(CH(CH 3 )CH 2 CH 3 ; R 3 is -(CH 2 J 6 -; Rr is -(CH 2 )*-; R 2 - and R 2 - are -CH(CH 3 ) 2 and R 3 - is -(CH 2 J 3 -.
- R 1 is -(CH 2 J 4 -; R 2 and R 2 - are -(CH(CH 3 )CH 2 CH 3 ; R 3 is -(CH 2 J 12 -; R 1 . is -(CH 2 ) 4 -; R 2 - and R 2 - are -CH(CH 3 J 2 and R 3 - is -(CH 2 J 3 -.
- R 1 is -(CH 2 ) S -;
- R 2 , R 2 -, R 2 - and R 2 - are -(CH(CH 3 )CH 2 CH 3 ;
- R 3 is -(CH 2 )6-;
- Rr is - (CH 2 ) 2 - and R 3 - is ⁇ (CH 2 ) 2 -.
- A is amorphous; B is crystalline; and the crosslink comprises inter-chain crystallization.
- Ri is -(CH 2 )S-;
- Rr is -(CH 2 J 4 ;
- R 2 and R 2 - are -CH 2 CH(CH 3 J 2 ;
- R 2 - and R 2 - are CH 2 phenyl;
- R 3 is -(CH 2 Je-; and,
- R 3 - is - (CH 2 J 4 -.
- At least the drug reservoir layer comprises a crosslinked poly(ester-amide) of this invention.
- at least the rate-controlling layer comprises a crosslinked poly(ester-amide) of this invention.
- At least the topcoat layer comprises a cross-linked poly(ester-amide) of this invention.
- an implantable medical device comprising: a device body; an optional primer layer disposed over the device body; a drug reservoir layer disposed over the device body or the primer layer if opted, wherein the drug reservoir layer comprises one or more therapeutic agents; an optional rate-controlling layer disposed over at least a portion of the drug reservoir layer, if opted; and, an optional top-coat layer disposed as an outermost layer over the device body, the primer layer, if opted, the drug reservoir layer, if opted, or the rate-limiting layer, if opted, wherein: at least one of the layers comprises a poly(ester-amide) having the formula:
- Mn is from about 10,000 Da to about 1 ,000,000 Da; s is a number from 0 to1 , inclusive; t is a number from 0 to 1 , inclusive; v is a number from 0 to 1 , inclusive; wherein s + 1 + v - 1 ;
- X has the chemical structure: R 2 R .r C ft-(Rv)-C Sf- HN-C Hp-C I?-O-(R 3 O-O-C ff- ⁇ H-N
- Y has the chemical structure: 1 V R2- ;
- Ri, Rv and R 4 are independently selected from the group consisting of (1C-12C)alkyl and (2C-12C)alkenyl;
- R2, Rz, R2 " and R ⁇ - are independently selected from the group consisting of hydrogen and (1C-4C)alkyI, wherein: the alkyl group is optionally substituted with a moiety selected from the group consisting of -OH, -O(1C-4C)alkyl, -SH, -S(1C-4C)alkyl, -SeH, -COR 6 , -NHC(NH)NH 2 , imidazol-2-yl, imidazole-5-yl, indol-3-yl, phenyl, 4-hydroxyphenyl and 4-[(1C-4C)alkylO]phenyl, wherein:
- R 2 " and R 2 - may form a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
- R 3 is selected from the group consisting of (1C-12C)alkyl and (2C- 12C)alkenyl, (3C-8C)cycloalkyl and -(CH 2 CH 2 O) q CH 2 CH 2 -;
- R 5 is selected from the group consisting Of -CH(CORe)CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 XCH 2 )4NH-, -(CH 2 J 4 CH(COR 6 )NH-, q is an integer from 1 to 600, inclusive.
- M n is from about 20,000 Da to about 500,000 Da.
- At least an outermost layer comprises the poly(ester-amide).
- the outermost layer is a topcoat layer.
- R 4 are selected from the group consisting of -(CH 2 ) 4 -and -(CH 2 J 8 -.
- R 2 is -CH 2 CH(CHa) 2 .
- R 3 is -(CH 2 ) ⁇ - and Ry is
- R 1 and R 4 are independently selected from the group consisting of -(CH 2 ) 4 - and -(CH 2 Ja-.
- R 2 and R 2 ' are independently selected from the group consisting of — CH 3 , -CH 2 CH 2 NHC(NH)NH 2 , -CH 2 CONH 2 , -CH 2 COOH, -CH 2 SH, -CH 2 CH 2 COOH,
- R 3 is selected from the group consisting of -(CH 2 J 3 -, -(CH 2 J 6 - and -(CH 2 CH 2 O JqCH 2 CH 2 -, wherein q is an integer from 1 to 10, inclusive.
- Re is selected from the group consisting of a stable nitroxide
- R 2 and R 2 - are identical.
- R 2 and R 2 - are -CH 2 CH(CH 3 )2.
- R 2 and R 2 - are selected from the group consisting of -CH 3 , -H 2 CH 2 NHC(NH)NH 2 , -CH 2 CONH 2 ,
- R 2 and R 2 - are the same.
- R 2 and R 2 - are CH 2 CH(CH 3 ) 2 .
- R 3 is selected from the group consisting of (3C-8C) alkyl, -(CH 2 CH 2 O) q CH 2 CH 2 -, wherein q is an integer
- R 2 and R ⁇ are benzyl.
- the implantable medical device further comprises a drug reservoir layer and a rate-controlling layer, wherein the rate- controlling layer comprises a polymer selected from the group consisting of poly(l-lactide), poly(D-lactide), poly(D,L-lactide), poly(meso-lactide), poly(L- lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(meso-lactide-co-glycolide) and an combination thereof.
- the rate- controlling layer comprises a polymer selected from the group consisting of poly(l-lactide), poly(D-lactide), poly(D,L-lactide), poly(meso-lactide), poly(L- lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(meso-lactide-co
- the rate-controlling layer comprises poly(D,L-lactide).
- the implantable medical device further comprises a drug reservoir layer, wherein the drug reservoir layer comprises one or more drugs disposed neat over the primer layer.
- the implantable medical device further comprises a drug reservoir layer, wherein the drug reservoir layer comprises one or more polymers.
- the therapeutic agent is everolimus.
- the drug reservoir layer polymer is selected from the group consisting of poly(vinylidene fluoride) and poly(vinylidene fluoride- co-hexafluoropropylene).
- the implantable medical device further comprises a primer layer, wherein the primer layer comprises poly(n-butyl methacrylate).
- An aspect of this invention is a stent, comprising a poly(n-butyl methacrylate) primer, a poly(vinylidene fluoride-co-hexafluoropropylene) drug reservoir layer comprising everolimus and a topcoat layer comprising a poly(ester-amide).
- the poly(ester-amide) in the aspect immediately above is selected from the group consisting of PEA-TEMPO and PEA-BZ.
- an outermost layer comprises the polyester- amide).
- the outermost layer is a topcoat layer.
- nitroxide is selected from the group consisting of V r ,
- q is 1 — 10, inclusive.
- q is 300 - 600, inclusive.
- the implantable medical device is a stent.
- Figure 1 graphically depicts the inflammatory and cellular response elicited by Impra ® graft material, Hemashield ® graft material, PEA-TEMPO and PEA-BZ at 14 days post-implantation in rat epicardial tissue.
- Figure 2 graphically depicts the inflammatory and cellular response elicited by Impra ® graft material, Hemashield ® graft material, PEA-TEMPO and PEA-BZ at 30 days post-implantation in rat epicardial tissue.
- Figure 3 graphically depicts endothelial cell coverage of a PEA-coated stent, a BMS and a Solef ® (poly(vinylidene fluoride-co-hexafluoropropylene)- coated stent.
- Figure 4 graphically depicts the percentage everolimus released by a stent without a topcoat, which establishes a target release rate, compared with a stent having a topcoat of a poly(ester-amide) of this invention. Discussion
- any words of approximation such as without limitation, "about,” “essentially,” “substantially” and the like mean that the element so modified need not be exactly what is described but can vary from the description by as much as ⁇ 15% without exceeding the scope of this invention.
- if opted means that the item being discussed is optional and if the option is exercised the condition that follows the phrase will pertain.
- a device body (db) that has coated on it an "optional” primer layer(pl), an "optional” drug reservoir layer (dr), an “optional” rate-controlling layer (re) and a top-coat layer (tc) refers, without limitation, to any of the following devices: db + tc, db + dr + tc, db + dr + re + tc, db + pi + tc, db + pi + dr + tc and db + pi + dr + re + tc.
- a poly(ester-amide) refers to a polymer that has in its backbone structure both ester and amide bonds.
- the following formulae represent poly(ester-amide)s of this invention:
- X, Y and Z refer to the constitutional units, i.e., the repeating units, of the polymer.
- the polymer in the polymer
- R 2 -C-COOH comprises the reaction of an amino acid, H , with a diol
- a diacid, HO-C-(R 1 J-C-OH 5 to give the constitutional unit.
- the amine group, the carboxylic acid group or the hydroxyl group may be "activated," i.e., rendered more chemically reactive, to facilitate the reactions if desired; such activating techniques are well-known in the art and the use of any such techniques is within the scope of this invention.
- a non-limiting example of the synthesis of an exemplary but not limiting X constitution unit having the above general structure is the reaction of 1 ,6-hexane diol with l-leucine to give the diamino diester, which is then /eacted with sebacic acid to give X.
- Constitutional unit Y can be obtained by the same reactions as those affording X but using one or more different reactants such that the resulting constitutional units X and Y are chemically different or Y may result from the reaction of a diacid with a tri- functional amino acid wherein two of the functional groups are capable of reacting with the diacid.
- a diacid with a tri- functional amino acid wherein two of the functional groups are capable of reacting with the diacid.
- two of the functional groups are capable of reacting with the diacid.
- l-lysine i.e., 2,6- diaminohexanoic acid.
- amino acids selected for the preparation of poly(ester-amide)s of this invention any may be use; however, at present it is preferred that the amino acids be selected from the group commonly known as the standard amino acids or sometimes the proteinogenic amino acids because they are encoded by the normal genetic code.
- the amino acids There currently are 20 standard amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenyl alanine, proline, serine, threonine, tryptophan, tyrosine and valine.
- m, p and n are integers that represent the average number of constitutional units X, Y and Z in an uninterrupted string or, if there is more than on, block; i.e., the number of X units before a Y unit is encountered, etc.
- the integers m, p and n can be any number, including 0; when two of m, p and n are 0, the resulting poly(ester-amide) is a homopolymer.
- k represents the total number of X and Y units in the polymer and r represents the total number of X, Y and Z units in the polymer.
- the value of k and r can be any integer from 1 to about 2500, with the proviso that the combination of m, n, p and k should provide a poly(ester-amide) that has a molecular weight within the range discussed below.
- M n represents the number average molecular weight of a poly(ester-amide) of this invention.
- the number average molecular weight of a poly(ester- amide) of this invention is from about 10,000 Da (Daltons) to about 1 ,000,000 Da, preferably at present from about 20,000 Da to about 500,000 Da.
- s, t and v represent the mole fraction of each of the constitutional units.
- the mole fraction and the number of constitutional units are obviously related and it is understood that the designation of one will affect the other.
- t and v may each be 0, 1 or any fraction between.
- certain provisos (1 ) if an additional prohealing entity is present on one of the constitutional units, that constitutional unit must be at least .02 mol fraction of the polymer; and (2) m and p can both be 0 only if R5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(C(O)R 6 CH 2 O-,
- any values of s, t and v that provides a polymer having desirable properties for the intended use, e.g., as a drug reservoir layer, a rate-controlling layer, etc., and those skilled in the art will be readily able to make such variations and determine if the resulting polymer as the requisite properties based on the disclosures herein without undue experimentation.
- s and t may each be 0, 1 or any fraction between.
- the only proviso is that m can be 0 only if R 5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(C(O)R 6 CH 2 O-, -CH(COR 6 )CH(CH 3 )O- and because otherwise the resulting homopolymer would not be a poly(ester-amide).
- m and n can be any number in the given range and those skilled in the art will be able, based on the disclosures herein, vary m and n to impart on the final polymer any type of desired property that varying the mole fractions can achieve depending on which type of layer, as set forth herein, is being contemplated.
- Constitutional unit Z is the result of the reaction of a diacid with a tri-functional amino acid wherein two of the functional groups are capable of reacting with the diacid.
- two of the functional groups are capable of reacting with the diacid.
- sebacic acid or an activated derivative thereof with l-lysine, 2, 6-diami ⁇ ohexanoic acid, the two amino groups being capable of reacting with the diacid carboxyl groups to form amides.
- poly(ester-amides) of this invention may be used as is, that is, as the product of amino acids, diacids and diols as described above because it has been found that the poly(ester-amide)s of this invention exhibit pro-healing properties in their own right. It is an aspect of this invention, however, that a poly(ester-amide) of this invention may be further modified by the attachment of an additional pro-healing moiety to an appropriate pendant group attached to the polymer backbone.
- pro-healing moiety is meant a substituent group that is biocompatible and that aids in the amelioration of inflammation and/or in the endothelialization of the implantable medical device.
- the polymers of this invention may be regular alternating polymers, random alternating polymers, regular block polymers, random block polymers or purely random polymers unless expressly stated to be otherwise.
- a regular alternating polymer has the general structure: ...x-y-z-x-y-z-x-y-z-...
- a random alternating polymer has the general structure: ...x-y-x-z-x-y-z-y-z-x-y-..., it being understood that the exact juxtaposition of the various constitution units may vary.
- a regular block polymer has the general structure: ...x-x-x-y-y-y-z-z-x-x...
- a random block polymer has the general structure: ...x-x-x-z-z-x-x-y-y-y-y-z- Z-Z-X-X-Z-Z-Z-...
- the juxtaposition of blocks, the number of constitutional units in each block and the number of blocks in a particular block polymer of this invention are not in any manner limited by the preceding illustrative generic structures.
- alkyl refers to a straight or branched chain fully saturated (no double or triple bonds) hydrocarbon (carbon and hydrogen only) group.
- alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopjppyl, cyclobutyl, cyclope ⁇ tyl, and cyclohexyl.
- alkyl includes “alkylene” groups, which refer to straight or branched fully saturated hydrocarbon groups having two rather than one open valences for bonding to other groups.
- alkylene groups include, but are not limited to methylene, -CH 2 -, ethylene, -CH 2 CH 2 -, propylene, -CH 2 CH 2 CH 2 -, n-butyle ⁇ e, - CH 2 CH 2 CH 2 CH 2 -, sec-butylene, -CH 2 CH 2 CH(CH 3 )- and the like.
- mC to nC refers to the number of possible carbon atoms in the indicated group. That is, the group can contain from “m” to "n", inclusive, carbon atoms.
- An alkyl group of this invention may comprise from 1 to 12 carbon atoms, that is, m is1 and n is 12. Of course, a particular alkyl group may be more limited. For instance without limitation, an alkyl group of this invention may consist of 3 to 8 carbon atoms, in which case it would be designated as a (3C-8C)alkyl group.
- the numbers are inclusive and incorporate all straight or branched chain structures having the indicated number of carbon atoms.
- a "Ci to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, CH 3 CH(CH 3 )-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 CH-.
- a cycloalkyl group refers to an alkyl group in which the end carbon atoms of the alkyl chain are covalently bonded to one another.
- the numbers “m” and “n” refer to the number of carbon atoms in the ring formed.
- a (3C-8C)cycloalkyl group refers to a three, four, five, six, seven or eight member ring, that is, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.
- bicycloalkyl refers to two cycloalkylgroups bonded together by a single covalent bond.
- bicycloalkyl group is bicyclohexane
- benzyl refers to a phenylmethylene, group.
- alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
- 0 refers to the structure — c-R as that is the only way the carbon can be tetravalent without the addition of hydrogen or other atoms no shown in the structure.
- stick structure exemplified by represents the structure that is, each terminus is capped with a CH3 group and the apex of each angle is a carbon atom with the requisite number of hydrogens attached.
- alkyl-i alkyl-i, alkyb, etc.
- alkyl groups may be the same or different.
- a “stable nitroxide” refers to an isolatable paramagnetic organic compound having the generic structure RR 1 N-O wherein R and R 1 may be aliphatic or may join to form a ring which may be acyclic or aromatic.
- the stable nitroxide must also contain at least one functional group through which the nitroxide may be covalently bonded to a poly(ester-amide) of this invention.
- 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl can be reacted with a pendant carboxylic acid group of, without limitation, lysine that comprises the backbone of a poly(ester-amide) of this invention, to form an amide.
- a pendant carboxylic acid group of, without limitation, lysine that comprises the backbone of a poly(ester-amide) of this invention can be reacted with a pendant carboxylic acid group of, without limitation, lysine that comprises the backbone of a poly(ester-amide) of this invention.
- Other such functional groups that will afford covalently bonded stable nitroxides will be evident to those skilled in the art based on the disclosures herein and are within the scope of this invention.
- to dispose a layer of "neat" therapeutic agent simply means that the therapeutic agent, once it is has been applied to a surface and any solvent used during the application has been allowed to evaporate, the therapeutic agent is the only constituent of the layer, i.e., there is essentially no solvent, no polymers, no excipients or any other material in the layer other than the therapeutic agent in essentially the same purity as it had before being applied to the device.
- the poly(ester-amides) of this invention have been found to have beneficial pro-healing properties in vivo, in particular with regard to inflammation and neovascularization.
- neovascularization kinetics of a stent coated with PEA-TEMPO was compared to that of a bare metal stent (BMS) and a poly(vinylidene fluoride-co-hexafluoropropylene) (SOLEF ® ) coated stent (Example 2) when the stents were implanted in a bioengineered vessel.
- BMS bare metal stent
- SOLEF ® poly(vinylidene fluoride-co-hexafluoropropylene)
- polyester- amide) polymers of this invention are quite biocompatible, it is expected that coating implantable medical devices with a topcoat of a poly(ester-amide) herein should have a substantial beneficial effect on healing in the vicinity of the implanted device and thereby reduce the occurrence of problems associated with slow healing such as late-stage thrombosis. This should be particularly valuable with regard to drug eluting stents (DESs), which were initially introduced to counter the high rate of restenosis among recipients of BMSs.
- DESs drug eluting stents
- BMSs while overcoming some of the shortfalls of percutaneous coronary angioplasty (PTCA), such as elastic recoil of the arterial wall resulting in dynamic re-narrowing of the vessel, BMSs were found to still be susceptible to restenosis, albeit at a substantially lower rate than unstented PTCAs (15 - 20% in stented patients versus 30 - 50% in previous unstented PTCAs).
- PTCA percutaneous coronary angioplasty
- the first DESs designed to address BMS restenosis were introduced. The stents were engineered to slowly releases cytostatic drug in the vicinity of the stent thereby slowing or preventing cell growth and resultant restenosis. DESs have reduced the incidence of restenosis to 5 - 7%.
- poly(ester-amide) of this invention may be incorporated into any of, any combination of, or all of the layers disposed over an implantable medical device of this invention, in one embodiment of this invention it is presently preferred that the poly(ester-amide) be included in at least the outermost layer coated on the device.
- outermost layer simply refers to that layer of material disposed over an implantable medical device of this invention that is in contact with bodily fluids and/or tissues of the patient in whom the device is implanted.
- the outermost layer is preferably at present a separate topcoat layer as described elsewhere herein but it may be a rate-controlling layer, if a topcoat layer is not opted, or even a drug reservoir layer if neither the topcoat layer nor the rate-controlling layer is opted.
- a poly(ester-amide) topcoat can be applied directly to the surface of a BMS.
- the healing characteristics of the poly(ester-amide) coating alone is expected to have a salutary effect on restenosis even without added therapeutic agent.
- polyester- amide in a drug reservoir layer with no further layers being applied. This may be the case if the release profile of the therapeutic agent is not deleteriously affected by the inclusion of the poly(ester-amide) in that layer. Techniques for determining if the release profile of a particular therapeutic agent is acceptable for a particular application is well within the knowledge of those skilled in the art and need not be further described herein.
- primers there may be layers disposed between the poly(ester-amide) topcoat and the device body.
- a common additional layer would be a primer as described above.
- a primer may be used if it is found that the material of which the device body is constructed does not adhere well to the selected polyester- amide). While many primer polymers and polymer blends are known in the art and any of them can be used with the devices and methods herein, a currently preferred class of primers is the acrylate polymers, copolymers and blends thereof. Preferable at present, poly(n-butyl methacrylate) is a preferred primer for use with the devices and methods of this invention.
- an implantable medical device of this invention may encompass a large array of devices
- a presently preferred device is a coronary stent and a presently preferred therapeutic agent for use with the stent is everolimus.
- an implantable medical device herein comprise a primer applied directly to the device body and then a drug reservoir layer comprising po!y(ethylidene fluoride) and everolimus, applied over the primer layer.
- a pro-healing poly(ester-amide) topcoat is then applied over the drug reservoir layer.
- a rate-controlling layer may be present but is not necessarily so in that it has been determined (data not shown) that certain formulations of poly(vinylidene fluoride-co-hexafluoropropylene)/everolimus drug reservoir layers exhibit desirable release profiles.
- a more detailed description of this aspect of this invention is provided in Example 3.
- a separate rate-controlling layer may be used.
- different rate-controlling polymers or polymer blends useful with different therapeutic agents are known in the art and all are within the scope of this invention so long as a poly(ester-amide) topcoat layer is applied as the outermost layer on the implantable device.
- everolimus is a presently preferred therapeutic agent for use herein.
- the presently preferred pro-healing poly(ester- amide)s, PEA-TEMPO and PEA-BZ are quite permeable to everolimus and cannot alone provide achieve desirable sustained-release profiles.
- a rate- controlling layer may be disposed atop the drug reservoir layer can be employed.
- polymers useful for establishing desired everolimus release profiles are poly(L-lactide), poly(D-lactide), poly(D.L-lactide), poly(meso-lactide), poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co- glycolide), poly(meso-lactide-co-glycolide) or any combination thereof. Most preferred at present in poly(D.L-lactide).
- a concrete, but in no way limiting, example of an implantable medical device that follows the above protocol would be: a 12 mm Vision ® stent;
- a crosslink refers to a small region in a macromolecule involving at least two discrete polymer chains and from which at least 4 chains emanate. Crosslinking results in the motion of the individual chains involved to be restricted with respect to other chains involved in the crosslink.
- a crosslink may comprise covalent or ionic links between the chains, which is referred to herein as a “chemical crosslink” or it may be the result of non-bonded interactions of regions of the individual chains, which are referred to herein as "physical crosslinks.”
- Covalent bond chemical crosslinks are created using chemical reactions well-known to those of ordinary skilJ in organic chemistry.
- covalent chemical crosslinks are of two types.
- the first type involves the reaction of a functional group appended to a polymer backbone with a multifunctional crosslinking agent.
- a "multifunctional crosslinking agent” is a compound having two or more functional groups that are capable of reacting with a functional group appended to the polymer backbone.
- the functional group appended to the polymer backbone can be a hydroxyl, -OH, group and the multifunctional crosslinking agent can be a diisocyanate.
- the cross-linking reaction is shown schematically in Scheme 1:
- the crosslink comprises a thiocarbamate, -SC(O)NH-.
- the crosslink comprises a urea, -NHC(O)NH-. If the hydroxyl is replaced by a carboxyl, -C(O)OH, group, the crosslink comprises an amide, -C(O)NH-, group.
- a non-limiting example of a chemically crosslinked segment of a poly(ester-amide) of this invention involving the reaction of an isocyanate and a carboxyl group is the following:
- Aziridines are known to react with active H + functional groups such as carboxyls as exemplified by the following non-limiting example (Scheme 3):
- the remaining aziridine group in the above product may, of course, also react with a polymer chain to give a three-way crosslink.
- Many other chemical crosslinking agents that can react with -OH, -SH, -Nhb and -C(O)OH groups are known to those skilled in the art and the use of any of them to crosslink poly(ester-amide)s is within the scope of this invention.
- ethylenic groups may be incorporated into the backbone of the polymer (Scheme 4):
- Scheme 5 shows a non-limiting example of a UV or free radical initiated crosslinked segment of a poly(ester-amide) of this invention:
- the ethylenic group may be incorporated in a group appended to the polymer backbone as shown in the following non-limiting example of yet another crosslinked poly(ester-amide) segment of this invention (Scheme 6):
- crosslinking reagent that itself has ethylenic groups.
- one of the MA-PEG-MA ethylenic groups reacts with an ethylenic groups of one polymer chain and the other ethylenic group of the MA-PEG-MA reacts with an ethylenic group of a different chain.
- the other type of chemical crosslink for the purposes of this invention is the formation of ionic bonds between metal cations (M +) and carboxyl anions, - C(O)O " , appended to the backbone of a poly(ester-amide) herein.
- Polymers crosslinked in this manner are referred to as ionomers.
- lonomers "cross-link" polymers by two mechanisms, although there is a great deal of overlap. The first mechanism occurs when a carboxylic acid, -C(O)OH 1 group appended to a polymer backbone is reacted with a divalent base, for example without limitation, Zn(OH) 2 .
- the clustering of ionic groups results from the phase separation of the fundamentally hydrophobic polymer backbone and the hydrophilic ionic groups, lonomers, however, are not formally crosslinked, which requires the formation of covalent bonds between polymer chains.
- the ionic clusters of ionomers can be relatively easily be disrupted by forces such as heating, which increases the both the degree and vigor of molecular motion in the polymer chains to the point that the clusters are dispersed.
- the clusters are primarily responsible for the physical properties of ionomers, which physical properties can, in some instances, be quite remarkable.
- ionomers can be extremely tough, so much so that they are often used to make products requiring great resiliency as the outer covering on golf balls.
- chemically crosslinked polymers of this invention can be of any type: homopolymers, alternating polymers, random alternating polymers, alternating block polymers, random block polymers or completely random polymers, physically crosslinked polymers of this invention must be block copolymers.
- the first kind of physically cross-linked poly(ester-amide) of this invention involves multi-block copolymers consisting of alternating hard and soft segments.
- Hard segments and soft segments are differentiated primarily by their glass transition temperatures, T 9 .
- T 9 is the temperature at which a polymer (or a segment of a polymer) changes mechanical properties from those of a rubber (i.e., elastic) to those of a glass (brittle).
- the polymeric molecules have very little translational freedom, i.e., they are unable to move easily or very far in relation to one another. Rather than moving around to adapt to an applied stress, they tend to separate violently so that the polymer breaks or shatters similarly to a pane of glass that is stressed.
- T 9 relatively facile segmental motion becomes possible and the polymer chains are able to move around and slip by one another such that when a stress is applied to the polymer it bends and flexes rather than breaks.
- the T 9 of the soft segment must be at or below the temperature of the intended operating environment, which is the body of a living mammal. While the normal body temperature of mammals differs considerably, the primary mammal to which this invention is presently intended to apply is humans, which have a normal body temperature of approximately 37 0 C. Thus, it is presently preferred that the soft segment of poly(ester-amides) of this invention have a T 9 at or below about 37 0 C such that, when placed in a human body, the soft segments will, when they equilibrate to body temperature, be in an elastic rather than glass-like mode.
- poly(ester-amide)s of this invention may be used with other mammals having quite different normal body temperatures from humans; those skilled in the art will be able to determine what the proper T g s should be for particular mammals based on the disclosure herein and all such polyester- amides) for use with any mammal are within the scope of this invention.
- the hard segments of the poly(ester-amides) of this invention must be in a brittle glass-like rather than elastic mode when subjected to mammalian body temperature in order to create in their working environment the soft segment/hard segment morphology necessary to engage in this manner of crosslinking.
- the hard segments have a T 9 that is above 37 0 C and, of course, above the T 9 of the soft segments. It is presently preferred that the hard segments of the poly(ester-amides) of this invention have a T 9 that is at least 5 0 C, preferably at least 15 °C and most preferably at present at least 25 0 C above the body temperature of the projected patients in whom the polymers are to be used.
- the degree of polymerization within the hard and soft segments is such that n and m are both greater than or equal to about 10. Further, while there is no absolute upper limit, it is presently preferred that the hard and soft segments have a degree of polymerization from about 10 to about 100.
- the block copolymer comprised of the foregoing hard and soft segments will preferably at present have a degree of polymerization at least an order of magnitude greater than the degree of polymerization within the segments.
- a poly(ester-amide) of this invention When subject to a temperature of about 37 0 C or higher (but below the T 9 of the hard segment), a poly(ester-amide) of this invention that meets the above criteria will phase separate into a soft-segment phase and a hard-segment phase due to chemical and physical incompatibility of the segments.
- the soft segments will remain in a random array of polymer chains and will retain their elastic properties.
- the hard segments due to their rigid structure, will tend to align with one another, that is, hard segments of different polymer chains will come together into what can be described as a paracrystalline structure. Paracrystalline simply means that the aligned segments display some short range order when examined by x-ray diffraction but they do not exhibit the intricate long range order of true crystals.
- the aligned hard segments held together by physical forces such as hydrogen bonding, van der Waals forces and the like, resist separation and act as multifunctional spacious crosslinked regions. It should be noted that the hard segments need not have any crystallinity whatsoever. Their T g s, which are above the operating temperature, together with the fact that they will phase separate into particular domains alone permits them to act as physical crosslinkers.
- Non-limiting examples of soft segment/hard segment poly(ester-amides) of this invention, together with the T g s of the segments are:
- a further type of physically crosslinked poly(ester-amide) of this invention comprises a unique subset of the preceding soft segment/hard segment polymer, namely, wherein the hard segment is crystalline.
- crystalline regions of polymers are substantially more robust and will maintain in a crosslinked configuration until the melting point, T m , which is a determinable number, of the crystalline regions is reached at which time the crystal structures "melt" similarly to small molecules crystals and become amorphous.
- T m 104 0 C
- T 9 59 0 C
- T 0 28 0 C
- an "implantable medical device” refers to any type of appliance that is totally or partly introduced, surgically or medically, into a patient's body or by medical intervention into a natural orifice, and which is intended to remain there after the procedure.
- the duration of implantation may be essentially permanent, i.e., intended to remain in place for the remaining lifespan of the patient; until the device biodegrades; or until it is physically removed.
- implantable medical devices include, without limitation, implantable cardiac pacemakers and defibrillators; leads and electrodes for the preceding; implantable organ stimulators such as nerve, bladder, sphincter and diaphragm stimulators, cochlear implants; prostheses, vascular grafts, self- expandable stents, balloon-expandable stents, stent-grafts, grafts, artificial heart valves and cerebrospinal fluid-shunts.
- An implantable medical device specifically designed and intended solely for the localized delivery of a therapeutic agent is within the scope of this invention.
- device body refers to an implantable medical in a fully formed utilitarian state with an outer surface to which no coating or layer of material different from that of which the device is manufactured has been applied.
- outer surface is meant any surface however spatially oriented that is in contact with bodily tissue or fluids.
- a common example of a “device body” is a BMS, i.e., a bare metal stent, which, as the name implies, is a fully-formed usable stent that has not been coated with a layer of any material different from the metal of which it is made on any surface that is in contact with bodily tissue or fluids.
- BMS i.e., a bare metal stent, which, as the name implies, is a fully-formed usable stent that has not been coated with a layer of any material different from the metal of which it is made on any surface that is in contact with bodily tissue or fluids.
- device body refers not only to BMSs but to any uncoated device regardless of what it is made
- Implantable medical devices made of virtually any material, i.e., materials presently known to be useful for the manufacture of implantable medical devices and materials that may be found to be so in the future, may be used with a coating of this invention.
- an implantable medical device useful with this invention may be made of one or more biocompatible metals or alloys thereof including, but not limited to, cobalt-chromium alloy (ELGILOY, L-605), cobalt-nickel alloy (MP-35N), 316L stainless steel, high nitrogen stainless steel, e.g., BIODUR 108, nickel-titanium alloy (NITINOL), tantalum, platinum, platinum-iridium alloy, gold and combinations thereof.
- cobalt-chromium alloy ELGILOY, L-605
- MP-35N cobalt-nickel alloy
- 316L stainless steel high nitrogen stainless steel, e.g., BIODUR 108, nickel-titanium alloy (NITINOL), tantalum, platinum, platinum-iridium alloy, gold
- Implantable medical devices may also be made of polymers that are biocompatible and biostable or biodegradable, the latter term including bioabsorbable and/or bioerodable.
- biocompatible refers to a polymer that both in its intact, that is, as synthesized, state and in its decomposed state, i.e., its degradation products, is not, or at least is minimally, toxic to living tissue; does not, or at least minimally and reparably, injure(s) living tissue; and/or does not, or at least minimally and/or controllably, cause(s) an immunological reaction in living tissue.
- relatively biostable polymers are, without limitation polyacrylates, polymethacryates, polyureas, polyurethanes, polyolefins, polyvinylhalides, polyvinylidenehalides, polyvinylethers, polyvinylaromatics, polyvinylesters, polyacrylonitriles, alkyd resins, polysiloxanes and epoxy resins.
- Biocompatible, biodegradable polymers include naturally-occurring polymers such as, without limitation, collagen, chitosan, alginate, fibrin, fibrinogen, cellulosics, starches, dextran, dextrin, hyaluronic acid, heparin, glycosaminoglycans, polysaccharides and elastin.
- One or more synthetic or semi-synthetic biocompatible, biodegradable polymers may also be used to fabricate an implantable medical device useful with this invention.
- a synthetic polymer refers to one that is created wholly in the laboratory while a semi-synthetic polymer refers to a naturally- occurring polymer than has been chemically modified in the laboratory.
- synthetic polymers include, without limitation, polyphosphazines, polyphosphoesters, polyphosphoester urethane, polyhydroxyacids, polyhydroxyalkanoates, polyanhyd rides, polyesters, polyorthoesters, polycarbonates, polyiminocarbonates, polyamino acids, polyoxymethylenes, poly(ester-amides) and polyimides.
- Blends and copolymers of the above polymers may also be used and are within the scope of this invention. Based on the disclosures herein, those skilled in the art will recognize those implantable medical devices and those materials from which they may be fabricated that will be useful with the coatings of this invention. At present, preferred implantable medical devices for use with the coatings of this invention are stents.
- a stent refers generally to any device used to hold tissue in place in a patient's body. Particularly useful stents, however, are those used for the maintenance of the patency of a vessel in a patient's body when the vessel is narrowed or closed due to diseases or disorders including, without limitation, tumors (in, for example, bile ducts, the esophagus, the trachea/bronchi, etc.), benign pancreatic disease, coronary artery disease, carotid artery disease and peripheral arterial disease such as atherosclerosis, restenosis and vulnerable plaque.
- Vulnerable plaque (VP) refers to a fatty build-up in an artery thought to be caused by inflammation.
- the VP is covered by a thin fibrous cap that can rupture leading to blood clot formation.
- a stent can be used to strengthen the wall of the vessel in the vicinity of the VP and act as a shield against such rupture.
- a stent can be used in, without limitation, neuro, carotid, coronary, pulmonary, aorta, renal, biliary, iliac, femoral and popliteal as well as other peripheral vasculatures.
- a stent can be used in the treatment or prevention of disorders such as, without limitation, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, chronic total occlusion, claudication, anastomotic proliferation, bile duct obstruction and ureter obstruction.
- disorders such as, without limitation, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, chronic total occlusion, claudication, anastomotic proliferation, bile duct obstruction and ureter obstruction.
- stents may also be employed for the localized delivery of therapeutic agents to specific treatment sites in a patient's body.
- therapeutic agent delivery may be the sole purpose of the stent or the stent may be primarily intended for another use such as those discussed above with drug delivery providing an ancillary benefit.
- a stent used for patency maintenance is usually delivered to the target site in a compressed state and then expanded to fit the vessel into which it has been inserted. Once at a target location, a stent may be self-expandable or balloon expandable. In any event, due to the expansion of the stent, any coating thereon must be flexible and capable of elongation.
- a material that is described as a layer “disposed over" an indicated substrate refers to a relatively thin coating of the material applied, preferably at present, directly to essentially the entire exposed surface of the indicated substrate.
- exposed surface is meant that surface of the substrate that, in use, would be in contact with bodily tissues or fluids.
- “Disposed over” may, however, also refer to the application of the thin layer of material to an intervening layer that has been applied to the substrate, wherein the material is applied in such a manner that, were the intervening layer not present, the material would cover substantially the entire exposed surface of the substrate.
- a primer layer refers to a coating consisting of a polymer or blend of polymers that exhibit good adhesion characteristics with regard to the material of which the device body is manufactured and good adhesion characteristic with regard to whatever material is to be coated on the device body.
- a primer layer serves as an adhesive intermediary layer between a device body and materials to be carried by the device body and is, therefore, applied directly to the device body.
- primers include silanes, titanates, zirconates, silicates, parylene, polyacrylates and polymethacrylates, with poly(n-butyl methacrylate) being a presently preferred primer.
- drug reservoir layer refers either to a layer of one or more therapeutic agents applied neat or to a layer of polymer or blend of polymers that has dispersed within its three-dimensional structure one or more therapeutic agents.
- a separate drug reservoir layer may be required if, without limitation, if is found that a desired therapeutic agent is not sufficiently compatible with the poly(ester-amide) to provide the desired agent concentration, if the desired release profile cannot be achieved, etc.
- the drug reservoir layer may comprise simply the drug alone, that is, neat. This can be accomplished by dissolving the drug in a suitable solvent, applying the solution atop a primer that has been coated on the device body, and removing the solvent leaving a layer of drug alone. The poly(ester-amide) topcoat may then be applied directly over the neat drug layer.
- the therapeutic agent may be formulated with a polymer or polymer blend.
- therapeutic agent and polymer can be dissolved in a suitable solvent or the polymer can be dissolved and the therapeutic agent evenly dispersed in the polymer solution.
- the solution or mixture can then be applied to either the device body or over a primer layer.
- the solvent is removed the drug is left suspended in polymer.
- the polymer or polymer blend is selected to provide the desired release profile.
- a polymer that is compatible with the drug may not afford the desired release profile or a polymer that can provide the desired profile is not sufficiently compatible with the drug. This situation may be ameliorated by the inclusion of a rate-controlling layer over the drug reservoir layer.
- therapeutic agent refers to any substance that, when administered in a therapeutically effective amount to a patient suffering from a disease, has a therapeutic beneficial effect on the health and well-being of the patient.
- a therapeutic beneficial effect on the health and well-being of a patient includes, but it not limited to: (1) curing the disease; (2) slowing the progress of the disease; (3) causing the disease to retrogress; or, (4) alleviating one or more symptoms of the disease.
- a therapeutic agent also includes any substance that when administered to a patient, known or suspected of being particularly susceptible to a disease, in a prophylactically effective amount, has a prophylactic beneficial effect on the health and well-being of the patient.
- a prophylactic beneficial effect on the health and well-being of a patient includes, but is not limited to: (1) preventing or delaying on-set of the disease in the first place; (2) maintaining a disease at a retrogressed level once such level has been achieved by a therapeutically effective amount of a substance, which may be the same as or different from the substance used in a prophylactically effective amount; or, (3) preventing or delaying recurrence of the disease after a course of treatment with a therapeutically effective amount of a substance, which may be the same as or different from the substance used in a prophylactically effective amount, has concluded.
- drug and “therapeutic agent” are used interchangeably.
- rate-controlling layer refers to a polymeric layer that is applied over a drug reservoir layer to modify the rate of release into the environment of the therapeutic agents from the drug reservoir layer.
- a rate- controlling layer may be used simply to "tune" the rate of release of a therapeutic agent to exactly that desired by the practitioner or it may be a necessary adjunct to the construct because the polymer or blend of polymers with which the therapeutic agent is compatible with regard to coating as a drug reservoir layer may be too permeable to the therapeutic substance resulting in too rapid release and delivery of the therapeutic substance into a patient's body.
- a non-limiting example is an everolimus drug reservoir layer comprising PEA-TEMPO (a poly(ester-amide) to which 2,2,6,6-tetramethyl-4-aminopiperidineoxyl has been covalently appended).
- PEA-TEMPO a poly(ester-amide) to which 2,2,6,6-tetramethyl-4-aminopiperidineoxyl has been covalently appended.
- PEA-TEMPO has very desirable in vivo properties, it is quite permeable to everolimus.
- sustained release i.e., release of a therapeutically effective amount of a drug over an extended period of time which may be a few days, a few months, or even longer
- everolimus from a poly(ester-amide) polymer matrix is difficult and in some cases impossible to achieve.
- a rate-controlling polymer or blend of polymers through which the everolimus must pass can be applied over the more PEA-TEMPO layer.
- the layer can comprise a polymer that, due to its inherent properties or because it has been cross-linked, presents a more difficult to traverse barrier to an eluting drug.
- the rate-controlling propensity of this layer will depend, without limitation, on such factors as the amount of this polymer in the layer, the thickness of the layer and the degree of cross-linking of the polymer.
- a “topcoat layer” refers to an outermost layer, that is, a layer that is in contact with the external environment and that is coated over all other layers.
- the topcoat layer may be applied to provide better hydrophilicity to the device, to better lubricate the device or merely as a device protectant.
- the topcoat layer may also contain therapeutic agents, in particular if the treatment protocol being employed calls for essentially immediate release of one or more therapeutic agent (these being included in the topcoat layer) followed by the controlled release of another therapeutic agent or agents over a longer period of time.
- the topcoat layer may contain one or more "biobeneficial agents.”
- an implantable medical device of this invention comprises at least a topcoat layer and that the topcoat layer comprise a, poly(ester-amide) as described herein.
- a "biobeneficial” agent is one that beneficially affects an implantable medical device by, for example, reducing the tendency of the device to protein foul, increasing the hemocompatibility of the device, and/or enhancing the non- thrombogenic, non-inflammatory, non-cytotoxic, non-hemolytic, etc. characteristics of the device.
- biobeneficial materials include, but are not limited to, polyethers such as poly(ethylene glycol) (PEG) and poly(propylene glycol); copoly(ether-esters) such as poly(ethylene oxide-co-lactic acid); polyalkylene oxides such as poly(ethylene oxide) and poly(propylene oxide); polyphosphazenes, phosphoryl choline, choline, polymers and copolymers of hydroxyl bearing monomers such as hydroxyethyl methacrylate, hydroxypropyl methacrylate, hydroxypropylmethacrylamide, poly (ethylene glycol) acrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone (VP); carboxylic acid bearing monomers such as methacrylic acid, acrylic acid, alkoxymethacrylate, alkoxyacrylate, and 3-trimethylsilylpropyl methacrylate; polystyrene-PEG, polyisobutylene
- An implantable medical device of this invention may include one or more therapeutic agents.
- Virtually any therapeutic agent found to be useful when incorporated on and implantable medical device may be used in the device and method of this invention.
- therapeutic agents include, but are not limited to anti-proliferative, anti-inflammatory, antineoplastic, antiplatelet, anti- coagulant, anti-fibrin, antithror ⁇ bonic, antimitotic, antibiotic, antiallergic and antioxidant compounds.
- the therapeutic agent may be, again without limitation, a synthetic inorganic or organic compound, a protein, a peptide, a polysaccharides and other sugars, a lipid, DNA and RNA nucleic acid sequences, an antisense oligonucleotide, an antibodies, a receptor ligands, an enzyme, an adhesion peptide, a blood clot agent such as streptokinase and tissue plasminogen activator, an antigen, a hormone, a growth factor, a ribozyme, a retroviral vector, an anti-proliferative agent such as rapamycin (sirolimus), 40-O- (2-hydroxyethyl)rapamycin (everolimus), 40-O-(3-hydroxypropyl)rapamycin, 40- O-(2-hydroxyethoxy)ethylrapamycin, 40-O-tetrazolylrapamycin, 40-epi(N1- tetrazolyl)
- therapeutic agents which are currently available or that may be developed in the future for use with implantable medical devices may likewise be used and all are within the scope of this invention.
- Presently preferred therapeutic agents for use with this invention are rapamycin (sirolimus), 40-O-(2-hydroxyethyl)rapamycin (everolimus), 40-O-(3- hydroxypropyl)rapamycin, 40-O-(2-hydroxyethoxy)ethylrapamcyin, 40-O- tetrazolylrapamycin and 40-epi(N1-tetrazolyl)rapamycin (zotarolimus, ABT-578).
- rapamycin sirolimus
- 40-O-(2-hydroxyethyl)rapamycin everolimus
- 40-O-(3- hydroxypropyl)rapamycin 40-O-(2-hydroxyethoxy)ethylrapamcyin
- the inflammatory response of PEA-TEMPO and PEA-BZ was evaluated using a rat epicardial model. Hemashield ® graft material was used as a highly inflammatory control and Impra ® ePTFE graft material was used as a minimally inflammatory control.
- Four millimeter diameter 300 ⁇ m thick discs of each polymer were implanted onto rat epicardial surface and the inflammation level was measured at 14 days and at 30 days. The control discs exhibited inflammatory and cellular responses typical of those materials.
- Both PEA- TEMPO and PEA-BZ exhibited cellular and inflammatory responses that were equal to or less than that of the Impra ® disc. The results are shown graphically in Figs. 1 and 2.
- the re-endothelializatio,n kinetics of PEA-TEMPO coated on a stent were compared to those of a bare metal stent (BMS) and a stent coated with Solef ® (poly(vinylidene fluoride-co-hexafluoropropylene).
- BMS bare metal stent
- Solef ® poly(vinylidene fluoride-co-hexafluoropropylene
- Medium Vision ® 4.0 X 18 mm stents were used bare, coated with 1494 /yg of PEA-TEMPO or coated with 767 ⁇ g of Solef ® .
- the stents were implanted in a bioengineered vessel and evaluated after 7 days.
- the stented vessels were stained with bisbenzimide (BBI), cut in half longitudinally and imaged with a 10X objective.
- BBI bisbenzimide
- a poly(ester-amide) topcoat was applied over a small 18 mm stent having a poly(n-butyl methacrylate) primer and a drug reservoir layer of poly(vinylidene fluoride-co-hexafluoropropylene) containing 190 ⁇ g of everolimus.
- the poly(ester-amide) used was PEA-TEMPO and 89 ⁇ g were applied to the stent over the drug reservoir layer.
- the release rate target of the stent absent the topcoat is shown on the right in Fig. 4.
- the release rate obtained with the PEA- TEMPO is shown on the left. As can be seen, the permissible standard deviations overlap, indicating that the PEA-TEMPO topcoat did not detrimentally interfere with the target release rate.
- a poly(ester-amide) topcoat layer on the mechanical integrity of the stent of Example 3 was examined.
- a small 18 mm Vision ® stent was coated with a poly(n-butyl methacrylate) primer and a drug reservoir layer of poly(vinylidene fluoride-co-hexafluoropropylene) containing 190 ⁇ g of everolimus.
- 89 ⁇ g of PEA-TEMPO was spray-coated from a 2 wt% solids absolute ethanol solution resulting in an approximately 0.92 ⁇ m thick coating of the poly(ester-amide).
- the coating was then examined post-wet expansion from an overall, an outside diameter and an inside diameter perspective. It was found that the PEA-TEMPO coating did not introduce any observable coating integrity failures on wet expansion.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Vascular Medicine (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Polymers & Plastics (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Materials For Medical Uses (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polyamides (AREA)
Abstract
La présente invention concerne des dispositifs médicaux implantables comprenant des élastomères de poly(ester-amide) disposés en couches de revêtement sur le dispositif. La présente invention concerne également des dispositifs médicaux implantables au sein desquels les poly(ester-amides) présentent des propriétés favorisant la guérison.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009519529A JP2009543897A (ja) | 2006-07-13 | 2007-07-12 | ポリ(エステル−アミド)、それらの誘導体、及び埋め込み型医療デバイスへのそれらの使用 |
EP07810387A EP2069421A1 (fr) | 2006-07-13 | 2007-07-12 | Poly(ester-amides), leurs dérivés et leur emploi dans des dispositifs médicaux implantables |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/487,059 US8030436B2 (en) | 2006-07-13 | 2006-07-13 | Poly(ester-amide) elastomers and their use with implantable medical devices |
US11/486,553 | 2006-07-13 | ||
US11/486,553 US7731987B2 (en) | 2006-07-13 | 2006-07-13 | Implantable medical device comprising a pro-healing poly(ester-amide) |
US11/487,059 | 2006-07-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2008008437A1 true WO2008008437A1 (fr) | 2008-01-17 |
Family
ID=38670619
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2007/015902 WO2008008437A1 (fr) | 2006-07-13 | 2007-07-12 | Poly(ester-amides), leurs dérivés et leur emploi dans des dispositifs médicaux implantables |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP2069421A1 (fr) |
JP (1) | JP2009543897A (fr) |
WO (1) | WO2008008437A1 (fr) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009114326A3 (fr) * | 2008-03-11 | 2010-06-17 | Abbott Cardiovascular Systems Inc. | Dispositif médical implantable comprenant un poly(ester-amide) favorisant la cicatrisation |
WO2010135739A3 (fr) * | 2009-05-22 | 2011-03-03 | Cornell Research Foundation, Inc. | Poly(ester amide)s et poly(ester éther amide)s ayant des groupes fonctionnels latéraux réticulables |
EP2784101A1 (fr) * | 2013-03-28 | 2014-10-01 | Nitto Europe N.V | Poly(ester-amide) fonctionnalisés d'hydroxyphényl |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101317414B1 (ko) | 2011-12-07 | 2013-10-10 | 현대자동차주식회사 | 핫 스탬핑 성형용 금형 및 그 제작방법 |
FR3010081B1 (fr) * | 2013-09-05 | 2017-11-17 | Centre Nat Rech Scient | Procede de synthese sequentielle de poly(alcoxyamine amide)s, copolymeres obtenus et leurs utilisations |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002018477A2 (fr) * | 2000-08-30 | 2002-03-07 | Cornell Research Foundation, Inc. | Copolyester amides et copolyester urethannes fonctionnels biodegradables et elastomeres |
US20050245637A1 (en) * | 2004-04-30 | 2005-11-03 | Hossainy Syed F A | Methods for modulating thermal and mechanical properties of coatings on implantable devices |
WO2005121250A2 (fr) * | 2004-06-03 | 2005-12-22 | Cornell Research Foundation, Inc. | Biomatieres de poly(ester-amide) insaturees |
-
2007
- 2007-07-12 WO PCT/US2007/015902 patent/WO2008008437A1/fr active Application Filing
- 2007-07-12 EP EP07810387A patent/EP2069421A1/fr not_active Withdrawn
- 2007-07-12 JP JP2009519529A patent/JP2009543897A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002018477A2 (fr) * | 2000-08-30 | 2002-03-07 | Cornell Research Foundation, Inc. | Copolyester amides et copolyester urethannes fonctionnels biodegradables et elastomeres |
US20050245637A1 (en) * | 2004-04-30 | 2005-11-03 | Hossainy Syed F A | Methods for modulating thermal and mechanical properties of coatings on implantable devices |
WO2005121250A2 (fr) * | 2004-06-03 | 2005-12-22 | Cornell Research Foundation, Inc. | Biomatieres de poly(ester-amide) insaturees |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009114326A3 (fr) * | 2008-03-11 | 2010-06-17 | Abbott Cardiovascular Systems Inc. | Dispositif médical implantable comprenant un poly(ester-amide) favorisant la cicatrisation |
WO2010135739A3 (fr) * | 2009-05-22 | 2011-03-03 | Cornell Research Foundation, Inc. | Poly(ester amide)s et poly(ester éther amide)s ayant des groupes fonctionnels latéraux réticulables |
EP2784101A1 (fr) * | 2013-03-28 | 2014-10-01 | Nitto Europe N.V | Poly(ester-amide) fonctionnalisés d'hydroxyphényl |
Also Published As
Publication number | Publication date |
---|---|
EP2069421A1 (fr) | 2009-06-17 |
JP2009543897A (ja) | 2009-12-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8034364B2 (en) | Implantable medical device comprising a pro-healing(ester-amide) | |
US8030436B2 (en) | Poly(ester-amide) elastomers and their use with implantable medical devices | |
US20060115449A1 (en) | Bioabsorbable, biobeneficial, tyrosine-based polymers for use in drug eluting stent coatings | |
US7632914B2 (en) | Biobeneficial polyamide/polyethylene glycol polymers for use with drug eluting stents | |
JP5368703B2 (ja) | 医療器具のためのメタクリレートコポリマー | |
US8808723B2 (en) | Polymers containing poly(ester amides) and agents for use with medical articles and methods of fabricating the same | |
US8377462B2 (en) | PEA-TEMPO/PEA-BZ coatings for controlled delivery of drug from implantable medical devices | |
JP5743287B2 (ja) | ビス−(アルファ−アミノ−ジオール−ジエステル)を含有するポリエステルアミドを含むコーティング | |
JP5365929B2 (ja) | ステレオコンプレックス形成組成物及びそれを含む埋め込み型医療機器 | |
JP2007520260A (ja) | 生体有益性コーティング組成物及びその製造方法及びその使用 | |
JP2009542852A (ja) | メタクリレート及びアクリレートのランダムコポリマー | |
JP6351617B2 (ja) | 薬物送達のためのポリエステルアミドコポリマーを含むコーティング | |
WO2008008334A2 (fr) | Dispositif médical implantable libérant progressivement un médicament comprenant un piégeur de radicaux libres servant à protéger les médicaments au cours de la stérilisation et procédé correspondant | |
US7795467B1 (en) | Bioabsorbable, biobeneficial polyurethanes for use in medical devices | |
US8323676B2 (en) | Poly(ester-amide) and poly(amide) coatings for implantable medical devices for controlled release of a protein or peptide and a hydrophobic drug | |
EP2069421A1 (fr) | Poly(ester-amides), leurs dérivés et leur emploi dans des dispositifs médicaux implantables | |
US20080014244A1 (en) | Implantable medical devices and coatings therefor comprising physically crosslinked block copolymers | |
JP5201486B2 (ja) | メトキシエチルメタクリレートのミッドブロックを含むブロックコポリマー | |
US20150174299A1 (en) | Biodegradable Poly(Ester-Amide) And Poly(Amide) Coatings For Implantable Medical Devices With Enhanced Bioabsorption Times | |
WO2009114326A2 (fr) | Dispositif médical implantable comprenant un poly(ester-amide) favorisant la cicatrisation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 07810387 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009519529 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2007810387 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: RU |