WO2009117241A2 - Controlled degradation of magnesium stents - Google Patents
Controlled degradation of magnesium stents Download PDFInfo
- Publication number
- WO2009117241A2 WO2009117241A2 PCT/US2009/035809 US2009035809W WO2009117241A2 WO 2009117241 A2 WO2009117241 A2 WO 2009117241A2 US 2009035809 W US2009035809 W US 2009035809W WO 2009117241 A2 WO2009117241 A2 WO 2009117241A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- stents
- polymeric material
- stent
- magnesium
- inhibitors
- Prior art date
Links
- 230000015556 catabolic process Effects 0.000 title claims abstract description 63
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 63
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 title claims abstract description 58
- 229910052749 magnesium Inorganic materials 0.000 title claims abstract description 50
- 239000011777 magnesium Substances 0.000 title claims abstract description 50
- 229920000642 polymer Polymers 0.000 claims abstract description 91
- 239000012867 bioactive agent Substances 0.000 claims abstract description 61
- 238000000576 coating method Methods 0.000 claims abstract description 39
- 239000011248 coating agent Substances 0.000 claims abstract description 35
- 239000000463 material Substances 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 18
- -1 poylglycolide Polymers 0.000 claims description 17
- 210000004027 cell Anatomy 0.000 claims description 13
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 12
- 108010016731 PPAR gamma Proteins 0.000 claims description 12
- 239000003112 inhibitor Substances 0.000 claims description 12
- 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 claims description 12
- 229960002930 sirolimus Drugs 0.000 claims description 12
- 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 claims description 12
- 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 11
- 229910000861 Mg alloy Inorganic materials 0.000 claims description 10
- 239000004952 Polyamide Chemical class 0.000 claims description 10
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[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 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 229960005167 everolimus Drugs 0.000 claims description 10
- 229920002647 polyamide Chemical class 0.000 claims description 10
- 229960000235 temsirolimus Drugs 0.000 claims description 10
- 239000003242 anti bacterial agent Substances 0.000 claims description 9
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 9
- 229940088710 antibiotic agent Drugs 0.000 claims description 9
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims description 9
- 229940124302 mTOR inhibitor Drugs 0.000 claims description 9
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 claims description 9
- 102000039446 nucleic acids Human genes 0.000 claims description 9
- 108020004707 nucleic acids Proteins 0.000 claims description 9
- 150000007523 nucleic acids Chemical class 0.000 claims description 9
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 9
- 230000001028 anti-proliverative effect Effects 0.000 claims description 8
- 239000000017 hydrogel Substances 0.000 claims description 8
- 229920001610 polycaprolactone Chemical class 0.000 claims description 8
- 239000004632 polycaprolactone Chemical class 0.000 claims description 8
- 229940122361 Bisphosphonate Drugs 0.000 claims description 6
- 101800003838 Epidermal growth factor Proteins 0.000 claims description 6
- YACHGFWEQXFSBS-UHFFFAOYSA-N Leptomycin B Natural products OC(=O)C=C(C)CC(C)C(O)C(C)C(=O)C(C)C=C(C)C=CCC(C)C=C(CC)C=CC1OC(=O)C=CC1C YACHGFWEQXFSBS-UHFFFAOYSA-N 0.000 claims description 6
- 108010006519 Molecular Chaperones Proteins 0.000 claims description 6
- 102000000536 PPAR gamma Human genes 0.000 claims description 6
- 102000012132 Peroxisome proliferator-activated receptor gamma Human genes 0.000 claims description 6
- 229940079156 Proteasome inhibitor Drugs 0.000 claims description 6
- SSNQAUBBJYCSMY-UHFFFAOYSA-N aigialomycin A Natural products C12OC2CC(O)C(O)C(=O)C=CCC(C)OC(=O)C=2C1=CC(OC)=CC=2O SSNQAUBBJYCSMY-UHFFFAOYSA-N 0.000 claims description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 6
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 6
- 230000000692 anti-sense effect Effects 0.000 claims description 6
- 150000004663 bisphosphonates Chemical class 0.000 claims description 6
- 229940116977 epidermal growth factor Drugs 0.000 claims description 6
- 229940011871 estrogen Drugs 0.000 claims description 6
- 239000000262 estrogen Substances 0.000 claims description 6
- SSNQAUBBJYCSMY-KNTMUCJRSA-N hypothemycin Chemical compound O([C@@H](C)C\C=C/C(=O)[C@@H](O)[C@@H](O)C[C@H]1O[C@@H]11)C(=O)C=2C1=CC(OC)=CC=2O SSNQAUBBJYCSMY-KNTMUCJRSA-N 0.000 claims description 6
- YACHGFWEQXFSBS-XYERBDPFSA-N leptomycin B Chemical compound OC(=O)/C=C(C)/C[C@H](C)[C@@H](O)[C@H](C)C(=O)[C@H](C)/C=C(\C)/C=C/C[C@@H](C)/C=C(/CC)\C=C\[C@@H]1OC(=O)C=C[C@@H]1C YACHGFWEQXFSBS-XYERBDPFSA-N 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 229960003753 nitric oxide Drugs 0.000 claims description 6
- 239000002773 nucleotide Substances 0.000 claims description 6
- 125000003729 nucleotide group Chemical group 0.000 claims description 6
- 239000003207 proteasome inhibitor Substances 0.000 claims description 6
- 230000001131 transforming effect Effects 0.000 claims description 6
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 6
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 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 claims description 5
- 150000004676 glycans Chemical class 0.000 claims description 5
- 239000005014 poly(hydroxyalkanoate) Substances 0.000 claims description 5
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 5
- 229920000058 polyacrylate Polymers 0.000 claims description 5
- 229920000728 polyester Polymers 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 229920000903 polyhydroxyalkanoate Polymers 0.000 claims description 5
- 229920001282 polysaccharide Polymers 0.000 claims description 5
- 239000005017 polysaccharide Substances 0.000 claims description 5
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 5
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 5
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 5
- 229920001290 polyvinyl ester Chemical class 0.000 claims description 5
- 102000004169 proteins and genes Human genes 0.000 claims description 5
- 108090000623 proteins and genes Proteins 0.000 claims description 5
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 claims description 5
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical class O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims description 5
- 150000002009 diols Chemical group 0.000 claims description 4
- 239000002861 polymer material Substances 0.000 claims description 4
- CGTADGCBEXYWNE-GTTQIJKGSA-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-GTTQIJKGSA-N 0.000 claims description 4
- 230000000979 retarding effect Effects 0.000 claims description 2
- 102000009024 Epidermal Growth Factor Human genes 0.000 claims 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 5
- 229920002988 biodegradable polymer Polymers 0.000 abstract description 4
- 239000004621 biodegradable polymer Substances 0.000 abstract description 4
- 230000008030 elimination Effects 0.000 abstract description 3
- 238000003379 elimination reaction Methods 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 229910052751 metal Inorganic materials 0.000 description 10
- 239000002184 metal Substances 0.000 description 10
- 230000002792 vascular Effects 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000013270 controlled release Methods 0.000 description 7
- 230000002209 hydrophobic effect Effects 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910045601 alloy Inorganic materials 0.000 description 6
- 239000000956 alloy Substances 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 210000001367 artery Anatomy 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 102400001368 Epidermal growth factor Human genes 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- 108010006877 Tacrolimus Binding Protein 1A Proteins 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000000824 cytostatic agent Chemical class 0.000 description 3
- 230000001085 cytostatic effect Effects 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 230000000593 degrading effect Effects 0.000 description 3
- 229920001477 hydrophilic polymer Polymers 0.000 description 3
- 229920001600 hydrophobic polymer Polymers 0.000 description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 208000037803 restenosis Diseases 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 231100000167 toxic agent Toxicity 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102100027913 Peptidyl-prolyl cis-trans isomerase FKBP1A Human genes 0.000 description 2
- 208000032594 Vascular Remodeling Diseases 0.000 description 2
- 206010053648 Vascular occlusion Diseases 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 208000037976 chronic inflammation Diseases 0.000 description 2
- 230000006020 chronic inflammation Effects 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 238000002591 computed tomography Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 230000037353 metabolic pathway Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000007634 remodeling Methods 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 208000021331 vascular occlusion disease Diseases 0.000 description 2
- 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 2
- 229950009819 zotarolimus Drugs 0.000 description 2
- PTBDIHRZYDMNKB-UHFFFAOYSA-N 2,2-Bis(hydroxymethyl)propionic acid Chemical compound OCC(C)(CO)C(O)=O PTBDIHRZYDMNKB-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008238 biochemical pathway Effects 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 229920001688 coating polymer Polymers 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Chemical group 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 230000005660 hydrophilic surface Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000012977 invasive surgical procedure Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- 238000012667 polymer degradation Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 238000012154 short term therapy Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000002885 thrombogenetic effect Effects 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
Classifications
-
- 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
- A61L31/02—Inorganic materials
- A61L31/022—Metals or alloys
-
- 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
- A61L31/148—Materials at least partially resorbable by the body
-
- 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
- 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
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/432—Inhibitors, antagonists
Definitions
- Medical devices are described herein comprising magnesium based core structures whose elimination times are controlled by the appropriate polymer coating.
- Appropriate biodegradable polymers are selected which are suitable to provide a slower elimination time for the magnesium based core structure.
- implantable medical devices are intended to serve long term therapeutic applications and are not removed once implanted. In some cases it may be desirable to use implantable medical devices for short term therapies. Their removal, however, may require highly invasive surgical procedures that place the patient at risk for life threatening complications. It would be desirable to have medical devices designed for short term applications that degrade via normal metabolic pathways and are reabsorbed into the surrounding tissues. [0003] Additionally, recent advances in in situ drug delivery have led to the development of implantable medical devices specifically designed to provide therapeutic compositions to remote anatomical locations. Perhaps one of the most exciting areas of in situ drug delivery is in the field of interventional cardiology.
- vascular occlusions leading to ischemic heart disease are frequently treated using percutaneous transluminal coronary angioplasty (PTCA) whereby a dilation catheter is inserted through a femoral artery incision and directed to the site of the vascular occlusion. The catheter is dilated and the expanding catheter tip (the balloon) opens the occluded artery restoring vascular patency.
- PTCA percutaneous transluminal coronary angioplasty
- a vascular stent is deployed at the treatment site to minimize vascular recoil and restenosis. In some cases, however, stent deployment leads to damage to the intimal lining of the artery which may result in vascular smooth muscle cell hyperproliferation and restenosis. When restenosis occurs it is necessary to either re-dilate the artery at the treatment site, or, if that is not possible, a surgical coronary artery bypass procedure must be performed.
- Stents useful for restoring and maintaining patency in biological lumens, can be manufactured from a variety of materials. These materials include, but are not limited to, metals and polymers. Both metal and polymer vascular stents have been associated with thrombosis and chronic inflammation at the implantation site and impaired remodeling at the stent site. It has been proposed that limiting the exposure of the vessel to the stent to the immediate intervention period would reduce late thrombosis and chronic inflammation.
- One means to produce a temporary stent is to implant a bioabsorbable, or biodegradable, stent.
- bioabsorbable material for stent manufacture There are several parameters to consider in the selection of a bioabsorbable material for stent manufacture.
- bioactive agents include, but are not limited to, the strength of the material to avoid potential immediate recoil, the rate of degradation and corrosion, biocompatibility with the vessel wall and lack of toxicity. Additionally, it may be desirable to include bioactive agents in the bioabsorbable stent such that the bioactive agent is release at the implantation site during degradation of the stent.
- the mechanical properties and release profiles of bioactive agents directly depend on the rate of degradation of the stent material which is controlled by selection of the stent materials, passivation agents and the manufacturing process of the stent.
- bioabsorbable stents polymers and metals.
- Metal bioabsorbable stents are attractive since they have the potential to perform similarly to stainless steel metal stents.
- One such material is magnesium and bioresorbable magnesium alloy stents have been shown to induce less thrombosis in damaged arteries than conventional bare metal stents.
- Stents that have sufficient strength to hold the artery open and then dissolve in short periods of time, less than twelve months, are considered desirable.
- Current degradable stents use a polymer based construction that takes longer than one year to degrade and requires large thick struts which limit deliverability.
- Magnesium based stents have been shown to have acceptable crossing profiles (e.g.
- bioabsorbable stent which incorporates the strength (e.g. radial strength) characteristics of a metal stent, the drug eluting properties of a polymer based stent and a desirable controlled degradation time.
- Implantable medical devices more specifically stents, are described herein comprising magnesium based core structures whose degradation times are controlled by an appropriate polymer coating.
- Appropriate biodegradable polymers are selected which are suitable to provide a specific degradation time for the magnesium based core structure.
- Bioactive agents are incorporated into the polymer coating in order to aid in the therapeutic effect of the stent.
- stents comprising a magnesium based core structure, the core structure having a degradation time; a polymeric material associated with the core structure, the polymeric material having an ability to slow the degradation time; and a bioactive agent associated with the polymeric material.
- stents comprising: (a) a magnesium based core structure, the core structure having a first degradation time; (b) at least one polymeric material coated on at least a portion of the core structure, said polymeric material having an ability to slow said degradation time such that said polymeric material coated on at least a portion of the core has a second degradation time; and (c) at least one bioactive agent associated with the at least one polymeric material.
- the stent is selected from the group consisting of woven stents, individual ring stents, sequential ring stents, closed cell stents, open cell stents, laser cut tube stents, ratchet stents, and modular stents.
- the magnesium based core structure comprises magnesium and magnesium alloys.
- the second degradation time is between 1 month and 12 months.
- the polymeric material comprises a top coat.
- the at least one polymeric material comprises polymers selected from the group consisting of polylactide, poylglycolide, polysaccharides, proteins, polyesters, polyhydroxyalkanoates, polyalkelene esters, polyamides, polycaprolactone, polyvinyl esters, polyamide esters, polyvinyl alcohols, modified derivatives of caprolactone polymers, polytrimethylene carbonate, polyacrylates, polyethylene glyCOl, hydrOg ⁇ lS, phOtO-CUrable hy C ⁇ Documents and Sett ⁇ ngs ⁇ msg ⁇ Desktop ⁇ PatApp template doc combinations thereof.
- the at least one bioactive agent is selected from the group consisting of anti-proliferatives, mTOR inhibitors, estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, leptomycin B, peroxisome proliferator-activated receptor gamma ligands (PPAR ⁇ ), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, proteasome inhibitors, antibiotics, antiinflammatories, anti-sense nucleotides, transforming nucleic acids, sirolimus (rapamycin), tacrolimus (FK506), everolimus (certican), temsirolimus (CCI-779) and zotarolimus (ABT-578).
- the at least one bioactive agent is coated on said polymeric material.
- the at least one bioactive agent is dispersed within said polymer material.
- Described herein is a method of prolonging the life of an implantable magnesium based medical device comprising: (a) providing a magnesium based core structure comprising a first degradation time; (b) choosing at least one appropriate bioabsorbable polymeric material; (c) coating at least a portion of the core structure with the polymeric material forming a coated medical device, thereby retarding the degradation of the core structure; and (d) providing a medical device having a second degradation time.
- the magnesium based core structure comprises magnesium and magnesium alloys.
- the first degradation time is less than 1 month. In another embodiment, the second degradation time is between 1 month and 12 months.
- the at least one polymeric material is bioabsorbable and comprises polymers selected from the group consisting of polylactide, poylglycolide, polysaccharides, proteins, polyesters, polyhydroxyalkanoates, polyalkelene esters, polyamides, polycaprolactone, polyvinyl esters, polyamide esters, polyvinyl alcohols, modified derivatives of caprolactone polymers, polytrimethylene carbonate, polyacrylates, polyethylene glycol, hydrogels, photo- curable hydrogels, terminal diols, and combinations thereof.
- the at least one polymeric material is a top coat.
- the bioactive agent is selected from the group consisting of anti-proliferatives, mTOR inhibitors, estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, leptomycin B, peroxisome proliferator-activated receptor gamma ligands (PPAR ⁇ ), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, proteasome inhibitors, antibiotics, anti-inflammatories, anti-sense nucleotides, transforming nucleic acids, sirolimus (rapamycin), tacrolimus (FK506), everolimus (certican), temsirolimus (CCI-779) and zotarolimus (ABT-578).
- the bioactive agent is coated on the at least one polymeric material.
- the bioactive agent is dispersed within the at least one polymer material.
- the implantable medical device is selected from the group consisting of woven stents, individual ring stents, sequential ring stents, closed cell stents, open cell stents, laser cut tube stents, ratchet stents, and modular stents.
- Biocompatible As used herein “biocompatible” shall mean any material that does not cause injury or death to the animal or induce an adverse reaction in an animal when placed in intimate contact with the animal's tissues. Adverse reactions include inflammation, infection, fibrotic tissue formation, cell death, or thrombosis.
- Bioabsorbable As used herein "bioabsorbable” refers to a material that is biocompatible and subject to being broken down in vivo through the action of normal biochemical pathways. From time-to-time bioresorbable and biodegradable may be used interchangeably, however they are not coextensive. Biodegradable polymers may or may not be reabsorbed into surrounding tissues, however all bioabsorbable polymers are considered biodegradable.
- Controlled release refers to the release of a bioactive compound from a medical device surface at a predetermined rate. Controlled release implies that the bioactive compound does not come off the medical device surface sporadically in an unpredictable fashion and does not "burst" off of the device upon contact with a biological environment (also referred to herein as first order kinetics) unless specifically intended to do so. However, the term “controlled release” as used herein does not preclude a "burst phenomenon" associated with deployment. In some embodiments of the present invention an initial burst of drug may be desirable followed by a more gradual release thereafter.
- the release rate may be steady state (commonly referred to as "timed release” or zero order kinetics), that is the drug is released in even amounts over a predetermined time (with or without an initial burst phase) or may be a gradient release.
- a gradient release implies that the concentration of drug released from the device surface changes over time.
- compatible refers to a composition posing the optimum, or near optimum combination of physical, chemical, biological and drug release kinetic properties suitable for a controlled-release coating made in accordance with the teachings of the present invention.
- Physical characteristics include durability and elasticity/ductility, chemical characteristics include solubility and/or miscibility and biological characteristics include biocompatibility.
- the drug release kinetic should be either near zero-order or a combination of first and zero- order kinetics.
- Delayed Release refers to the release of bioactive agent(s) after a period of time and/or after an event or series of events.
- Drug or bioactive agent As used herein “drug” or “bioactive agent” shall include any agent having a therapeutic effect in an animal.
- anti-proliferatives including, but not limited to, macrolide antibiotics including FKBP 12 binding compounds, mTOR inhibitors, estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, leptomycin B, peroxisome proliferator-activated receptor gamma ligands (PPAR ⁇ ), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, proteasome inhibitors, antibiotics, anti-inflammatories, anti-sense nucleotides and transforming nucleic acids, cytostatic compounds, toxic compounds, antiinflammatory compounds, chemotherapeutic agents, analgesics, antibiotics, protease inhibitors, statins, nucleic acids, polypeptides, and delivery vectors including recombinant micro-organisms, liposomes, the like.
- macrolide antibiotics including FKBP 12 binding compounds
- mTOR inhibitors including FKBP 12 binding compounds
- Medical devices are described herein comprising magnesium based core structures whose degradation times can be controlled by an appropriate polymer coating.
- Appropriate bioabsorbable polymers can be selected which are suitable to provide a slower degradation time for the magnesium based core structure.
- the bioabsorbable polymers can also be used as a means of controlled release of a bioactive agent.
- the implantable medical device is a stent.
- the stent architectures suitable for fabrication are not limited to the examples provided herein but can include coil stents, helical spiral stents, woven stents, individual ring stents, sequential ring stents, closed cell stents, open cell stents, laser cut tube stents, ratcheting stents, modular stents and the like.
- stents adapted for deployment in any vessel or duct to maintain patency including, but not limited to vascular stents, stent grafts, biliary stents, esophageal stents, and stents of the trachea or large bronchi, ureters, and urethra are also consider within the scope of the present description.
- the stents comprise a magnesium based core.
- Magnesium and its alloys are biocompatible, bioabsorbable and easy to mechanically manipulate presenting an attractive solution for bioabsorbable stents. Radiological advantages of magnesium include compatibility with magnetic resonance imaging (MRI), magnetic resonance angiography and computed tomography (CT).
- MRI magnetic resonance imaging
- CT computed tomography
- Vascular stents comprising magnesium and its alloys are less thrombogenic than other bare metal stents.
- the biocompatibility of magnesium and its alloys stems from its relative non-toxicity to cells. Magnesium is abundant in tissues of animals and plants; specifically, magnesium is the fourth most abundant metal ion in cells, the most abundant free divalent ion and therefore is deeply and intrinsically woven into cellular metabolism.
- Magnesium-dependent enzymes appear in virtually every metabolic pathway is also used as a signaling molecule.
- Magnesium alloys suitable for bioabsorbable stents include alloys of magnesium with other metals including, but not limited to, aluminum and zinc. In one embodiment, the magnesium alloy comprises between about 1% and about 10% aluminum and between about 0.5% and about 5% zinc.
- the magnesium alloys can include but are not limited to Sumitomo Electronic Industries (SEI, Osaka, Japan) magnesium alloys AZ31 (3% aluminum, 1% zinc and 96% magnesium) and AZ61 (6% aluminum, 1% zinc and 93% magnesium).
- SEI Sumitomo Electronic Industries
- AZ31 3% aluminum, 1% zinc and 96% magnesium
- AZ61 6% aluminum, 1% zinc and 93% magnesium
- the desirable features of the alloy include high tensile strength and responsive ductility. Tensile strength of typical AZ31 alloy is at least 280 MPa while that of AZ61 alloy is at least 330 MPa.
- bioabsorbable polymers can be coated onto at least a portion of the stent.
- Suitable bioabsorbable polymers include, but are not limited to, polylactide, poylglycolide, polysaccharides, proteins, polyesters, polyhydroxyalkanoates, polyalkelene esters, polyamides, polycaprolactone, polyvinyl esters, polyamide esters, polyvinyl alcohols, modified derivatives of caprolactone polymers, polytrimethylene carbonate, polyacrylates, polyethylene glycol, hydrogels, photo-curable hydrogels, terminal diols, co-polymers of 2 or more of the above and combinations thereof.
- Varying the monomer ratios allows the ordinarily skilled artisan to fine tune, or to modify, the properties of the polymer.
- the properties of bioabsorbable polymers arise from the monomers used and the reaction conditions employed in their synthesis including but not limited to, temperature, solvents, reaction time and catalyst choice.
- a variety of properties are considered including, but not limited to, T 9 , connectivity, molecular weight, thermal properties, and degradation time.
- T 9 glass transition temperature of the bioabsorbable polymers
- Bioactive agent elution from polymers depends on many factors including density, the bioactive agent to be eluted, molecular composition of the polymer and T 9 .
- Higher T 9 S for example temperatures above 40 0 C, result in more brittle polymers while lower T 9 S, e.g lower than 40 0 C, result in more pliable and elastic polymers at higher temperatures.
- Bioactive agent elution is slow from polymers that have high T 9 S while faster rates of bioactive agent elution are observed with polymers possessing low T 9 S.
- the T 9 of the polymer is selected to be lower than 37°C.
- Polymers used for coating having relatively high T 9 S can result in medical devices with unsuitable drug eluting properties as well as unwanted brittleness.
- a relatively low T 9 in the coating polymer effects the deployment of the vascular stent.
- polymer coatings with low T 9 S are "sticky" and adhere to the balloon used to expand the vascular stent during deployment, causing problems with the deployment of the stent.
- Low T 9 polymers have beneficial features in that polymers having low TgS are more elastic at a given temperature than polymers having higher T g s. Expanding and contracting a polymer-coated vascular stent mechanically stresses the coating.
- the coating is too brittle, i.e. has a relatively high T 9 , then fractures may result in the coating possibly rendering the coating inoperable. If the coating is elastic, i.e has a relatively low T 9 , then the stresses experienced by the coating are less likely to mechanically alter the structural integrity of the coating. Therefore, the TgS of the polymers can be fine tuned for appropriate coating applications by a combination of monomer composition and synthesis conditions.
- the polymers are engineered to have adjustable physical properties enabling the practitioner to choose the appropriate polymer for the function desired.
- T 9 molecular weight (both M n and M w ), polydispersity index (PDI, the quotient of M w /M n ), degree of elasticity and degree of amphiphlicity.
- T 9 of the polymers range from about -10 0 C to about 85 0 C.
- PDI of the polymers range from about 1.35 to about 4.
- the T 9 of the polymers ranges form about 0 0 C to about 4O 0 C.
- the PDI of the polymers range from about 1.5 to about 2.5.
- Different polymers used to coat medical devices can have different degradation times in a cardiovascular (in vivo) environment. Functional groups, methods of polymer coordination, catalysts, polymer molecular weight, and hydrophobicity can all be relied upon to develop a polymer for coating onto an implantable medical device that has a tailored degradation time.
- the polymers can be applied to the magnesium based core as a top coat. As a top coat, the polymers restrict the body fluids, enzymes and cells from degrading the magnesium core. As a result, the degradation time of the stent can be extended by at least the time required to degrade the polymer.
- multiple polymeric layers can be applied to the magnesium based core.
- the other most layer can be considered the top coat.
- polymers can be utilized that will be most compatible with the surrounding tissue as the surrounding tissue develops around the stent.
- a polymer that aids in supporting the radial strength of the stent may be used as a first coat and thereon are layered one or more additional polymer coatings that are more biocompatible.
- Degradation times for bare magnesium stents are about one month.
- the first degradation time of the bare magnesium stent can be increased by application of a polymeric coating on the stent, the polymeric material having a second degradation time longer than that of the first degradation time. The over all degradation time of the polymeric material and the magnesium stent is thereby increased to a new degradation time longer than that of the two separately.
- the new degradation time is less than 6 months.
- the new degradation time is less than 12 months.
- the new degradation time is less than 9 months.
- the new degradation time is between about 1 month and about 3 months.
- the new degradation time is between about 1 month and about 6 months.
- the new degradation time is between about 1 month and about 9 months. In another embodiment, the new degradation time is between about 1 month and about 12 months. In another embodiment, the new degradation time is between about 3 months and about 9 months. In another embodiment, the new degradation time is between about 6 months and about 9 months. In another embodiment, the new degradation time is between about 3 months and about 12 months. In another embodiment, the new degradation time is between about 6 months and about 12 months. [0041] In another embodiment, only selected portions of the magnesium core are coated. In such a scenario, only selected portions of the core that are coated have an increased degradation time. The remaining portions of the magnesium core which are uncoated will degrade at the normal rate of a bare magnesium stent.
- different regions of the magnesium core can be coated with different polymer combinations.
- different portions of the magnesium core can be tailored to degrade at different rates which are dependent on the polymer used to coat that specific portion.
- limitless combinations of coatings can be applied to the magnesium core.
- bioabsorbable magnesium stents of the present invention are also useful for the delivery and controlled release of bioactive agents.
- Bioactive agents that are suitable for release from the stents include, but are not limited to, anti- proliferative compounds, cytostatic compounds, toxic compounds, anti-inflammatory compounds, chemotherapeutic agents, analgesics, antibiotics, protease inhibitors, statins, nucleic acids, polypeptides, growth factors and delivery vectors including recombinant micro-organisms, liposomes, and the like.
- the polymeric materials discussed herein may be designed to provide local delivery of a specific dose of bioactive agent. That dose may be a specific weight of bioactive agent added or a bioactive agent to polymer ratio.
- the medical device can be loaded with 0 to 1000 ⁇ g of bioactive agent; in another embodiment, 5 ⁇ g to 500 ⁇ g; in another embodiment 10 ⁇ g to 250 ⁇ g; in another embodiment, 15 ⁇ g 150 ⁇ g.
- a ratio may also be established to describe how much bioactive agent is added to the polymer that is coated to the medical device.
- a ratio of 1 part bioactive agent: 1 part polymer may be used; in another embodiment, 1 :1-5; in another embodiment, 1 :1-9; in another embodiment, 1 :1-20.
- bioactive agents include antiproliferatives including, but not limited to, macrolide antibiotics including FKBP-12 binding compounds, mTOR inhibitors estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, leptomycin B, peroxisome proliferator- activated receptor gamma ligands (PPAR ⁇ ), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, proteasome inhibitors, antibiotics, anti-inflammatories, anti-sense nucleotides and transforming nucleic acids.
- macrolide antibiotics including FKBP-12 binding compounds
- mTOR inhibitors estrogens
- chaperone inhibitors protease inhibitors
- protein-tyrosine kinase inhibitors protein-tyrosine kinase inhibitors
- leptomycin B leptomycin B
- PPAR ⁇ peroxisome proliferator- activated receptor gamma ligands
- Drugs can also refer to bioactive agents including anti-proliferative compounds, cytostatic compounds, toxic compounds, anti-inflammatory compounds, chemotherapeutic agents, analgesics, antibiotics, protease inhibitors, statins, nucleic acids, polypeptides, growth factors and delivery vectors including recombinant microorganisms, liposomes, and the like.
- Exemplary FKBP-12 binding agents include sirolimus (rapamycin), tacrolimus (FK506), everolimus (certican or RAD-001 ), temsirolimus (CCI-779 or amorphous rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid as disclosed in USPASN 10/930,487) and zotarolimus (ABT-578; see USPNs 6,015,815 and 6,329,386). Additionally, other rapamycin hydroxyesters as disclosed in USPN 5,362,718 may be used in combination with the polymers described herein.
- the implantable medical devices discussed herein can accommodate one or more additional bioactive agents.
- bioactive agent to incorporate, or how much to incorporate, will have a great deal to do with the polymer selected to coat or form the implantable medical device.
- hydrophobic agents are generally attracted to hydrophobic polymers and hydrophilic agents are generally attracted to hydrophilic polymers.
- the polymeric coating is hydrophilic and the bioactive agent is hydrophilic.
- the polymeric coating is hydrophobic and the bioactive agent is hydrophobic.
- the polymer coating can comprise a mixture of hydrophilic and hydrophobic polymers or a polymeric material comprising a mixture of hydrophobic and hydrophilic monomers.
- a blend of hydrophobic and hydrophilic polymers is coated onto the medical device.
- a blend coating such as this can exhibit properties such as, but not limited to, a hydrophobic core to accommodate hydrophobic bioactive agents and a hydrophilic surface to increase the biocompatibility of the coated device.
- the bioactive agent is covalently bonded to the bioabsorbable polymer.
- the covalently-bound bioactive agent is released in situ from the degrading polymer with the polymer degradation products thereby ensuring a controlled bioactive agent supply throughout the degradation course.
- the bioactive agent is released to the treatment site as the polymeric material is exposed through biodegradation.
- the bioactive agent is contained within pores or reservoirs within the bioabsorbable polymer and is released in situ from the degrading polymer thereby ensuring a controlled bioactive agent supply throughout the degradation course.
- multiple polymeric layers can be coated on the magnesium stent core. At least one of the polymeric layers can contain a bioactive agent. Bioactive agents can be coated with appropriate polymers to increase or decrease their respective elution times from the stent. Layers can be used on top of the bioactive agent containing polymer layers to retard the delivery of the bioactive agent even further or even block it from being delivered for a predetermined times based on the polymer or polymers used.
- one or more polymeric layers which contain one or more bioactive agents can be coated on the magnesium core. Coated on top can be one or more polymeric layers used to extent stent degradation time. In another embodiment, one or more polymeric layers which can be used to extent stent degradation time can be coated on the magnesium core. Coated on top can be coated one or more polymeric layers which contain one or more bioactive agents.
- Magnesium stents are placed in a glass beaker and covered with reagent grade or better hexane.
- the beaker containing the hexane immersed stents is then placed into an ultrasonic water bath and treated for 15 minutes at a frequency of between approximately 25 to 50 KHz.
- Next the stents are removed from the hexane and the hexane is discarded.
- the stents are then immersed in reagent grade or better 2-propanol and vessel containing the stents and the 2-propanol is treated in an ultrasonic water bath as before.
- the stents with organic solvents are thoroughly washed with distilled water and thereafter immersed in 1.0 N sodium hydroxide solution and treated at in an ultrasonic water bath as before. Finally, the stents are removed from the sodium hydroxide, thoroughly rinsed in distilled water and then dried in a vacuum oven over night at 4O 0 C. After cooling the dried stents to room temperature in a desiccated environment they are weighed their weights are recorded.
- ethanol is chosen as the solvent of choice; the polymer is soluble in tetrahydrofuran (THF).
- THF tetrahydrofuran
- Persons having ordinary skill in the art of polymer chemistry can easily pair the appropriate solvent system to the polymer and achieve optimum results with no more than routine experimentation.
- 250 mg of polycaprolactone (PCL) is added to the 2.8 ml_ of THF and mixed until the PCL is dissolved and a polymer solution is generated.
- the cleaned, dried stents are coated using either spraying techniques or dipped into the polymer solution. The stents are coated as necessary to achieve a final coating weight of between approximately 10 ⁇ g to 1 mg.
- the coated stents are dried in a vacuum oven at 50°C over night. The dried, coated stents are weighed and the weights recorded.
- the resulting polymer coating can have a degradation time of about 3 months.
- a stent can be coated first with the polymeric coating described in Example 2 and then by the polymeric material described in Example 3.
- the two polymeric layers can have a combined degradation time of about 9 months.
- a stent with a polymeric coating according to Example 2 can further include a bioactive agent dispersed within the polymer to be coated.
- a bioactive agent dispersed within the polymer to be coated.
- an mTOR inhibitor can be added to the polymeric material to be coated.
- the stent can be dipped into the polymeric material/bioactive agent blend thereby coating the blend onto the stent.
- a stent with a polymeric coating according to Example 3 can further include a bioactive agent dispersed within the polymer to be coated.
- a bioactive agent dispersed within the polymer to be coated.
- an mTOR inhibitor can be added to the polymeric material to be coated.
- the stent can be dipped into the polymeric material/bioactive agent blend thereby coating the blend onto the stent.
- EXAMPLE 7 A stent as described in Example 5 can be further dipped into a polymeric material/bioactive agent blend of Example 6. The resulting stent will have a combined degradation time of at least 9 months and can elute an mTOR inhibitor from both coatings.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Surgery (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Materials For Medical Uses (AREA)
Abstract
Implantable medical devices, more specifically stents, are described herein comprising magnesium based core structures whose elimination times are slowed by the appropriate polymer coating. Appropriate biodegradable polymers are selected which are suitable to provide a specific degradation time for the magnesium based core structure. Bioactive agents are incorporated into the polymer coating in order to aid in the therapeutic effect of the stent.
Description
CONTROLLED DEGRADATION OF MAGNESIUM STENTS
FIELD OF THE INVENTION
[0001] Medical devices are described herein comprising magnesium based core structures whose elimination times are controlled by the appropriate polymer coating. Appropriate biodegradable polymers are selected which are suitable to provide a slower elimination time for the magnesium based core structure.
BACKGROUND OF THE INVENTION
[0002] Generally, implantable medical devices are intended to serve long term therapeutic applications and are not removed once implanted. In some cases it may be desirable to use implantable medical devices for short term therapies. Their removal, however, may require highly invasive surgical procedures that place the patient at risk for life threatening complications. It would be desirable to have medical devices designed for short term applications that degrade via normal metabolic pathways and are reabsorbed into the surrounding tissues. [0003] Additionally, recent advances in in situ drug delivery have led to the development of implantable medical devices specifically designed to provide therapeutic compositions to remote anatomical locations. Perhaps one of the most exciting areas of in situ drug delivery is in the field of interventional cardiology. Vascular occlusions leading to ischemic heart disease are frequently treated using percutaneous transluminal coronary angioplasty (PTCA) whereby a dilation catheter is inserted through a femoral artery incision and directed to the site of the vascular occlusion. The catheter is dilated and the expanding catheter tip (the balloon) opens the occluded artery restoring vascular patency. Generally, a vascular stent is deployed at the treatment site to minimize vascular recoil and restenosis. In some cases, however, stent deployment leads to damage to the intimal lining of the artery which may result in vascular smooth muscle cell hyperproliferation and restenosis. When restenosis occurs it is necessary to either re-dilate the artery at the treatment site, or, if that is not possible, a surgical coronary artery bypass procedure must be performed.
[0004] Stents, useful for restoring and maintaining patency in biological lumens, can be manufactured from a variety of materials. These materials include, but are not limited to, metals and polymers. Both metal and polymer vascular stents have been associated with thrombosis and chronic inflammation at the implantation site
and impaired remodeling at the stent site. It has been proposed that limiting the exposure of the vessel to the stent to the immediate intervention period would reduce late thrombosis and chronic inflammation. One means to produce a temporary stent is to implant a bioabsorbable, or biodegradable, stent. [0005] There are several parameters to consider in the selection of a bioabsorbable material for stent manufacture. These include, but are not limited to, the strength of the material to avoid potential immediate recoil, the rate of degradation and corrosion, biocompatibility with the vessel wall and lack of toxicity. Additionally, it may be desirable to include bioactive agents in the bioabsorbable stent such that the bioactive agent is release at the implantation site during degradation of the stent. The mechanical properties and release profiles of bioactive agents directly depend on the rate of degradation of the stent material which is controlled by selection of the stent materials, passivation agents and the manufacturing process of the stent. Currently there are two types of materials used in bioabsorbable stents, polymers and metals.
[0006] Metal bioabsorbable stents are attractive since they have the potential to perform similarly to stainless steel metal stents. One such material is magnesium and bioresorbable magnesium alloy stents have been shown to induce less thrombosis in damaged arteries than conventional bare metal stents. [0007] Stents that have sufficient strength to hold the artery open and then dissolve in short periods of time, less than twelve months, are considered desirable. Current degradable stents use a polymer based construction that takes longer than one year to degrade and requires large thick struts which limit deliverability. Magnesium based stents have been shown to have acceptable crossing profiles (e.g. balloon expandable) and radial strength but bare magnesium has been shown to degrade too rapidly to be useful in arterial remodeling. Current magnesium based stents have a degradation time of about one month. Such magnesium stents which degrade is one month or less have been shown to be subject to constructive vascular remodeling. Constructive vascular remodeling has contributed to late loss and target lesion revascularization. For a degradable stent to be considered desirable, it will have to maintain a sufficient radial strength for greater than one month.
[0008] Therefore, there exists a need for a bioabsorbable stent which incorporates the strength (e.g. radial strength) characteristics of a metal stent, the
drug eluting properties of a polymer based stent and a desirable controlled degradation time.
SUMMARY OF THE INVENTION
[0009] Implantable medical devices, more specifically stents, are described herein comprising magnesium based core structures whose degradation times are controlled by an appropriate polymer coating. Appropriate biodegradable polymers are selected which are suitable to provide a specific degradation time for the magnesium based core structure. Bioactive agents are incorporated into the polymer coating in order to aid in the therapeutic effect of the stent. [0010] Described herein are stents comprising a magnesium based core structure, the core structure having a degradation time; a polymeric material associated with the core structure, the polymeric material having an ability to slow the degradation time; and a bioactive agent associated with the polymeric material. [0011] Described herein are stents comprising: (a) a magnesium based core structure, the core structure having a first degradation time; (b) at least one polymeric material coated on at least a portion of the core structure, said polymeric material having an ability to slow said degradation time such that said polymeric material coated on at least a portion of the core has a second degradation time; and (c) at least one bioactive agent associated with the at least one polymeric material. In one embodiment, the stent is selected from the group consisting of woven stents, individual ring stents, sequential ring stents, closed cell stents, open cell stents, laser cut tube stents, ratchet stents, and modular stents.
[0012] In one embodiment, the magnesium based core structure comprises magnesium and magnesium alloys. In another embodiment, the second degradation time is between 1 month and 12 months.
[0013] In one embodiment, the polymeric material comprises a top coat. In one embodiment, the at least one polymeric material comprises polymers selected from the group consisting of polylactide, poylglycolide, polysaccharides, proteins, polyesters, polyhydroxyalkanoates, polyalkelene esters, polyamides, polycaprolactone, polyvinyl esters, polyamide esters, polyvinyl alcohols, modified derivatives of caprolactone polymers, polytrimethylene carbonate, polyacrylates, polyethylene glyCOl, hydrOgβlS, phOtO-CUrable hy C \Documents and Settιngs\msg\Desktop\PatApp template doc combinations thereof.
[0014] in one embodiment, the at least one bioactive agent is selected from the group consisting of anti-proliferatives, mTOR inhibitors, estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, leptomycin B, peroxisome proliferator-activated receptor gamma ligands (PPARγ), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, proteasome inhibitors, antibiotics, antiinflammatories, anti-sense nucleotides, transforming nucleic acids, sirolimus (rapamycin), tacrolimus (FK506), everolimus (certican), temsirolimus (CCI-779) and zotarolimus (ABT-578). In another embodiment, the at least one bioactive agent is coated on said polymeric material. In another embodiment, the at least one bioactive agent is dispersed within said polymer material.
[0015] Described herein is a method of prolonging the life of an implantable magnesium based medical device comprising: (a) providing a magnesium based core structure comprising a first degradation time; (b) choosing at least one appropriate bioabsorbable polymeric material; (c) coating at least a portion of the core structure with the polymeric material forming a coated medical device, thereby retarding the degradation of the core structure; and (d) providing a medical device having a second degradation time. In one embodiment, the magnesium based core structure comprises magnesium and magnesium alloys.
[0016] In one embodiment, the first degradation time is less than 1 month. In another embodiment, the second degradation time is between 1 month and 12 months.
[0017] In one embodiment, the at least one polymeric material is bioabsorbable and comprises polymers selected from the group consisting of polylactide, poylglycolide, polysaccharides, proteins, polyesters, polyhydroxyalkanoates, polyalkelene esters, polyamides, polycaprolactone, polyvinyl esters, polyamide esters, polyvinyl alcohols, modified derivatives of caprolactone polymers, polytrimethylene carbonate, polyacrylates, polyethylene glycol, hydrogels, photo- curable hydrogels, terminal diols, and combinations thereof. In another embodiment, the at least one polymeric material is a top coat.
[0018] In one embodiment, the bioactive agent is selected from the group consisting of anti-proliferatives, mTOR inhibitors, estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, leptomycin B, peroxisome
proliferator-activated receptor gamma ligands (PPARγ), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, proteasome inhibitors, antibiotics, anti-inflammatories, anti-sense nucleotides, transforming nucleic acids, sirolimus (rapamycin), tacrolimus (FK506), everolimus (certican), temsirolimus (CCI-779) and zotarolimus (ABT-578). In another embodiment, the bioactive agent is coated on the at least one polymeric material. In another embodiment, the bioactive agent is dispersed within the at least one polymer material.
[0019] In one embodiment, the implantable medical device is selected from the group consisting of woven stents, individual ring stents, sequential ring stents, closed cell stents, open cell stents, laser cut tube stents, ratchet stents, and modular stents.
Definition of Terms
[0020] Before proceeding it may be useful to define many of the terms used to describe the present invention. Words and terms of art used herein should be first defined as provided for in this specification, and then as needed as one skilled in the art would ordinarily define the terms.
[0021] Biocompatible: As used herein "biocompatible" shall mean any material that does not cause injury or death to the animal or induce an adverse reaction in an animal when placed in intimate contact with the animal's tissues. Adverse reactions include inflammation, infection, fibrotic tissue formation, cell death, or thrombosis. [0022] Bioabsorbable: As used herein "bioabsorbable" refers to a material that is biocompatible and subject to being broken down in vivo through the action of normal biochemical pathways. From time-to-time bioresorbable and biodegradable may be used interchangeably, however they are not coextensive. Biodegradable polymers may or may not be reabsorbed into surrounding tissues, however all bioabsorbable polymers are considered biodegradable.
[0023] Controlled release: As used herein "controlled release" refers to the release of a bioactive compound from a medical device surface at a predetermined rate. Controlled release implies that the bioactive compound does not come off the medical device surface sporadically in an unpredictable fashion and does not "burst" off of the device upon contact with a biological environment (also referred to herein as first order kinetics) unless specifically intended to do so. However, the term "controlled release" as used herein does not preclude a "burst phenomenon"
associated with deployment. In some embodiments of the present invention an initial burst of drug may be desirable followed by a more gradual release thereafter. The release rate may be steady state (commonly referred to as "timed release" or zero order kinetics), that is the drug is released in even amounts over a predetermined time (with or without an initial burst phase) or may be a gradient release. A gradient release implies that the concentration of drug released from the device surface changes over time.
[0024] Compatible: As used herein "compatible" refers to a composition posing the optimum, or near optimum combination of physical, chemical, biological and drug release kinetic properties suitable for a controlled-release coating made in accordance with the teachings of the present invention. Physical characteristics include durability and elasticity/ductility, chemical characteristics include solubility and/or miscibility and biological characteristics include biocompatibility. The drug release kinetic should be either near zero-order or a combination of first and zero- order kinetics.
[0025] Delayed Release: As used herein "delayed release" refers to the release of bioactive agent(s) after a period of time and/or after an event or series of events. [0026] Drug or bioactive agent: As used herein "drug" or "bioactive agent" shall include any agent having a therapeutic effect in an animal. Exemplary, non limiting examples include anti-proliferatives including, but not limited to, macrolide antibiotics including FKBP 12 binding compounds, mTOR inhibitors, estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, leptomycin B, peroxisome proliferator-activated receptor gamma ligands (PPARγ), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, proteasome inhibitors, antibiotics, anti-inflammatories, anti-sense nucleotides and transforming nucleic acids, cytostatic compounds, toxic compounds, antiinflammatory compounds, chemotherapeutic agents, analgesics, antibiotics, protease inhibitors, statins, nucleic acids, polypeptides, and delivery vectors including recombinant micro-organisms, liposomes, the like.
DETAILED DESCRIPTION OF THE INVENTION
[0027] Medical devices are described herein comprising magnesium based core structures whose degradation times can be controlled by an appropriate polymer coating. Appropriate bioabsorbable polymers can be selected which are suitable to
provide a slower degradation time for the magnesium based core structure. The bioabsorbable polymers can also be used as a means of controlled release of a bioactive agent.
[0028] In one embodiment, the implantable medical device is a stent. The stent architectures suitable for fabrication are not limited to the examples provided herein but can include coil stents, helical spiral stents, woven stents, individual ring stents, sequential ring stents, closed cell stents, open cell stents, laser cut tube stents, ratcheting stents, modular stents and the like. Additionally, stents adapted for deployment in any vessel or duct to maintain patency including, but not limited to vascular stents, stent grafts, biliary stents, esophageal stents, and stents of the trachea or large bronchi, ureters, and urethra are also consider within the scope of the present description.
[0029] In one embodiment, the stents comprise a magnesium based core. Magnesium and its alloys are biocompatible, bioabsorbable and easy to mechanically manipulate presenting an attractive solution for bioabsorbable stents. Radiological advantages of magnesium include compatibility with magnetic resonance imaging (MRI), magnetic resonance angiography and computed tomography (CT). Vascular stents comprising magnesium and its alloys are less thrombogenic than other bare metal stents. The biocompatibility of magnesium and its alloys stems from its relative non-toxicity to cells. Magnesium is abundant in tissues of animals and plants; specifically, magnesium is the fourth most abundant metal ion in cells, the most abundant free divalent ion and therefore is deeply and intrinsically woven into cellular metabolism. Magnesium-dependent enzymes appear in virtually every metabolic pathway is also used as a signaling molecule. [0030] Magnesium alloys suitable for bioabsorbable stents include alloys of magnesium with other metals including, but not limited to, aluminum and zinc. In one embodiment, the magnesium alloy comprises between about 1% and about 10% aluminum and between about 0.5% and about 5% zinc.
[0031] The magnesium alloys can include but are not limited to Sumitomo Electronic Industries (SEI, Osaka, Japan) magnesium alloys AZ31 (3% aluminum, 1% zinc and 96% magnesium) and AZ61 (6% aluminum, 1% zinc and 93% magnesium). The desirable features of the alloy include high tensile strength and responsive ductility. Tensile strength of typical AZ31 alloy is at least 280 MPa while that of AZ61 alloy is at least 330 MPa.
[0032] In order to increase the degradation time of the magnesium based cores of the stents described herein, bioabsorbable polymers can be coated onto at least a portion of the stent. Suitable bioabsorbable polymers include, but are not limited to, polylactide, poylglycolide, polysaccharides, proteins, polyesters, polyhydroxyalkanoates, polyalkelene esters, polyamides, polycaprolactone, polyvinyl esters, polyamide esters, polyvinyl alcohols, modified derivatives of caprolactone polymers, polytrimethylene carbonate, polyacrylates, polyethylene glycol, hydrogels, photo-curable hydrogels, terminal diols, co-polymers of 2 or more of the above and combinations thereof.
[0033] Varying the monomer ratios allows the ordinarily skilled artisan to fine tune, or to modify, the properties of the polymer. The properties of bioabsorbable polymers arise from the monomers used and the reaction conditions employed in their synthesis including but not limited to, temperature, solvents, reaction time and catalyst choice. In order to tune, or modify, the polymers, a variety of properties are considered including, but not limited to, T9, connectivity, molecular weight, thermal properties, and degradation time.
[0034] Fine tuning, or modifying, the glass transition temperature (T9) of the bioabsorbable polymers is also taken into account. Bioactive agent elution from polymers depends on many factors including density, the bioactive agent to be eluted, molecular composition of the polymer and T9. Higher T9S, for example temperatures above 400C, result in more brittle polymers while lower T9S, e.g lower than 400C, result in more pliable and elastic polymers at higher temperatures. Bioactive agent elution is slow from polymers that have high T9S while faster rates of bioactive agent elution are observed with polymers possessing low T9S. In one embodiment, the T9 of the polymer is selected to be lower than 37°C. [0035] Polymers used for coating having relatively high T9S can result in medical devices with unsuitable drug eluting properties as well as unwanted brittleness. In the cases of polymer-coated vascular stents, a relatively low T9 in the coating polymer effects the deployment of the vascular stent. For example, polymer coatings with low T9S are "sticky" and adhere to the balloon used to expand the vascular stent during deployment, causing problems with the deployment of the stent. Low T9 polymers, however, have beneficial features in that polymers having low TgS are more elastic at a given temperature than polymers having higher Tgs. Expanding and contracting a polymer-coated vascular stent mechanically stresses
the coating. If the coating is too brittle, i.e. has a relatively high T9, then fractures may result in the coating possibly rendering the coating inoperable. If the coating is elastic, i.e has a relatively low T9, then the stresses experienced by the coating are less likely to mechanically alter the structural integrity of the coating. Therefore, the TgS of the polymers can be fine tuned for appropriate coating applications by a combination of monomer composition and synthesis conditions. The polymers are engineered to have adjustable physical properties enabling the practitioner to choose the appropriate polymer for the function desired.
[0036] Medical devices, including implantable medical devices, are coated with the polymers disclosed herein and therefore the physical properties of the polymers are considered in light of the specific application at hand. Physical properties of the polymers can be fine tuned so that the polymers can optimally perform for their intended use. Properties that can be fine tuned, without limitation, include T9, molecular weight (both Mn and Mw), polydispersity index (PDI, the quotient of Mw/Mn), degree of elasticity and degree of amphiphlicity. In one embodiment, the T9 of the polymers range from about -100C to about 850C. In still another embodiment, the PDI of the polymers range from about 1.35 to about 4. In another embodiment, the T9 of the polymers ranges form about 00C to about 4O0C. In still another embodiment, the PDI of the polymers range from about 1.5 to about 2.5. [0037] Different polymers used to coat medical devices can have different degradation times in a cardiovascular (in vivo) environment. Functional groups, methods of polymer coordination, catalysts, polymer molecular weight, and hydrophobicity can all be relied upon to develop a polymer for coating onto an implantable medical device that has a tailored degradation time. [0038] In one embodiment, the polymers can be applied to the magnesium based core as a top coat. As a top coat, the polymers restrict the body fluids, enzymes and cells from degrading the magnesium core. As a result, the degradation time of the stent can be extended by at least the time required to degrade the polymer.
[0039] In another embodiment, multiple polymeric layers can be applied to the magnesium based core. The other most layer can be considered the top coat. In such an embodiment, for example, polymers can be utilized that will be most compatible with the surrounding tissue as the surrounding tissue develops around the stent. For example, a polymer that aids in supporting the radial strength of the
stent may be used as a first coat and thereon are layered one or more additional polymer coatings that are more biocompatible.
[0040] Degradation times for bare magnesium stents are about one month. In one embodiment, the first degradation time of the bare magnesium stent can be increased by application of a polymeric coating on the stent, the polymeric material having a second degradation time longer than that of the first degradation time. The over all degradation time of the polymeric material and the magnesium stent is thereby increased to a new degradation time longer than that of the two separately. In one embodiment, the new degradation time is less than 6 months. In another embodiment, the new degradation time is less than 12 months. In another embodiment, the new degradation time is less than 9 months. In another embodiment, the new degradation time is between about 1 month and about 3 months. In another embodiment, the new degradation time is between about 1 month and about 6 months. In another embodiment, the new degradation time is between about 1 month and about 9 months. In another embodiment, the new degradation time is between about 1 month and about 12 months. In another embodiment, the new degradation time is between about 3 months and about 9 months. In another embodiment, the new degradation time is between about 6 months and about 9 months. In another embodiment, the new degradation time is between about 3 months and about 12 months. In another embodiment, the new degradation time is between about 6 months and about 12 months. [0041] In another embodiment, only selected portions of the magnesium core are coated. In such a scenario, only selected portions of the core that are coated have an increased degradation time. The remaining portions of the magnesium core which are uncoated will degrade at the normal rate of a bare magnesium stent. [0042] In another embodiment, different regions of the magnesium core can be coated with different polymer combinations. In such a scenario, different portions of the magnesium core can be tailored to degrade at different rates which are dependent on the polymer used to coat that specific portion. In such an embodiment, limitless combinations of coatings can be applied to the magnesium core.
[0043] The bioabsorbable magnesium stents of the present invention are also useful for the delivery and controlled release of bioactive agents. Bioactive agents that are suitable for release from the stents include, but are not limited to, anti-
proliferative compounds, cytostatic compounds, toxic compounds, anti-inflammatory compounds, chemotherapeutic agents, analgesics, antibiotics, protease inhibitors, statins, nucleic acids, polypeptides, growth factors and delivery vectors including recombinant micro-organisms, liposomes, and the like.
[0044] The polymeric materials discussed herein may be designed to provide local delivery of a specific dose of bioactive agent. That dose may be a specific weight of bioactive agent added or a bioactive agent to polymer ratio. In one embodiment, the medical device can be loaded with 0 to 1000 μg of bioactive agent; in another embodiment, 5 μg to 500 μg; in another embodiment 10 μg to 250 μg; in another embodiment, 15 μg 150 μg. A ratio may also be established to describe how much bioactive agent is added to the polymer that is coated to the medical device. In one embodiment a ratio of 1 part bioactive agent: 1 part polymer may be used; in another embodiment, 1 :1-5; in another embodiment, 1 :1-9; in another embodiment, 1 :1-20.
[0045] Exemplary, non limiting examples of bioactive agents include antiproliferatives including, but not limited to, macrolide antibiotics including FKBP-12 binding compounds, mTOR inhibitors estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, leptomycin B, peroxisome proliferator- activated receptor gamma ligands (PPARγ), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, proteasome inhibitors, antibiotics, anti-inflammatories, anti-sense nucleotides and transforming nucleic acids. Drugs can also refer to bioactive agents including anti-proliferative compounds, cytostatic compounds, toxic compounds, anti-inflammatory compounds, chemotherapeutic agents, analgesics, antibiotics, protease inhibitors, statins, nucleic acids, polypeptides, growth factors and delivery vectors including recombinant microorganisms, liposomes, and the like.
[0046] Exemplary FKBP-12 binding agents include sirolimus (rapamycin), tacrolimus (FK506), everolimus (certican or RAD-001 ), temsirolimus (CCI-779 or amorphous rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid as disclosed in USPASN 10/930,487) and zotarolimus (ABT-578; see USPNs 6,015,815 and 6,329,386). Additionally, other rapamycin hydroxyesters as disclosed in USPN 5,362,718 may be used in combination with the polymers described herein.
[0047] In addition to the site specific delivery of bioactive agent, the implantable medical devices discussed herein can accommodate one or more additional bioactive agents. The choice of bioactive agent to incorporate, or how much to incorporate, will have a great deal to do with the polymer selected to coat or form the implantable medical device. A person skilled in the art will appreciate that hydrophobic agents are generally attracted to hydrophobic polymers and hydrophilic agents are generally attracted to hydrophilic polymers. In one embodiment, the polymeric coating is hydrophilic and the bioactive agent is hydrophilic. In another embodiment, the polymeric coating is hydrophobic and the bioactive agent is hydrophobic.
[0048] In one embodiment, the polymer coating can comprise a mixture of hydrophilic and hydrophobic polymers or a polymeric material comprising a mixture of hydrophobic and hydrophilic monomers. In one embodiment, a blend of hydrophobic and hydrophilic polymers is coated onto the medical device. A blend coating such as this can exhibit properties such as, but not limited to, a hydrophobic core to accommodate hydrophobic bioactive agents and a hydrophilic surface to increase the biocompatibility of the coated device.
[0049] In one embodiment, the bioactive agent is covalently bonded to the bioabsorbable polymer. The covalently-bound bioactive agent is released in situ from the degrading polymer with the polymer degradation products thereby ensuring a controlled bioactive agent supply throughout the degradation course. The bioactive agent is released to the treatment site as the polymeric material is exposed through biodegradation.
[0050] In another embodiment, the bioactive agent is contained within pores or reservoirs within the bioabsorbable polymer and is released in situ from the degrading polymer thereby ensuring a controlled bioactive agent supply throughout the degradation course.
[0051] In one embodiment, multiple polymeric layers can be coated on the magnesium stent core. At least one of the polymeric layers can contain a bioactive agent. Bioactive agents can be coated with appropriate polymers to increase or decrease their respective elution times from the stent. Layers can be used on top of the bioactive agent containing polymer layers to retard the delivery of the bioactive agent even further or even block it from being delivered for a predetermined times based on the polymer or polymers used.
[0052] In one embodiment, one or more polymeric layers which contain one or more bioactive agents can be coated on the magnesium core. Coated on top can be one or more polymeric layers used to extent stent degradation time. In another embodiment, one or more polymeric layers which can be used to extent stent degradation time can be coated on the magnesium core. Coated on top can be coated one or more polymeric layers which contain one or more bioactive agents.
Example 1
Metal Stent Cleaning Procedure
[0053] Magnesium stents are placed in a glass beaker and covered with reagent grade or better hexane. The beaker containing the hexane immersed stents is then placed into an ultrasonic water bath and treated for 15 minutes at a frequency of between approximately 25 to 50 KHz. Next the stents are removed from the hexane and the hexane is discarded. The stents are then immersed in reagent grade or better 2-propanol and vessel containing the stents and the 2-propanol is treated in an ultrasonic water bath as before. Following cleaning, the stents with organic solvents are thoroughly washed with distilled water and thereafter immersed in 1.0 N sodium hydroxide solution and treated at in an ultrasonic water bath as before. Finally, the stents are removed from the sodium hydroxide, thoroughly rinsed in distilled water and then dried in a vacuum oven over night at 4O0C. After cooling the dried stents to room temperature in a desiccated environment they are weighed their weights are recorded.
EXAMPLE 2
Coating a Clean, Dried Stent
[0054] In the following Example, ethanol is chosen as the solvent of choice; the polymer is soluble in tetrahydrofuran (THF). Persons having ordinary skill in the art of polymer chemistry can easily pair the appropriate solvent system to the polymer and achieve optimum results with no more than routine experimentation. [0055] 250 mg of polycaprolactone (PCL) is added to the 2.8 ml_ of THF and mixed until the PCL is dissolved and a polymer solution is generated. [0056] The cleaned, dried stents are coated using either spraying techniques or dipped into the polymer solution. The stents are coated as necessary to achieve a final coating weight of between approximately 10 μg to 1 mg. Finally, the coated
stents are dried in a vacuum oven at 50°C over night. The dried, coated stents are weighed and the weights recorded. The resulting polymer coating can have a degradation time of about 3 months.
EXAMPLE 3
Coating a Clean, Dried Stent
[0057] 250 mg of poly-D-lactide (PDL) is added to the 2.8 ml_ of THF and mixed until the PDL is dissolved and a polymer solution is generated. [0058] The cleaned, dried stents are coated using either spraying techniques or dipped into the polymer solution. The stents are coated as necessary to achieve a final coating weight of between approximately 10 μg to 1 mg. Finally, the coated stents are dried in a vacuum oven at 500C over night. The dried, coated stents are weighed and the weights recorded. The resulting polymer coating can have a degradation time of about 6 months.
EXAMPLE 4
[0059] A stent can be coated first with the polymeric coating described in Example 2 and then by the polymeric material described in Example 3. The two polymeric layers can have a combined degradation time of about 9 months.
EXAMPLE 5
[0060] A stent with a polymeric coating according to Example 2 can further include a bioactive agent dispersed within the polymer to be coated. For example, an mTOR inhibitor can be added to the polymeric material to be coated. The stent can be dipped into the polymeric material/bioactive agent blend thereby coating the blend onto the stent.
EXAMPLE 6
[0061] A stent with a polymeric coating according to Example 3 can further include a bioactive agent dispersed within the polymer to be coated. For example, an mTOR inhibitor can be added to the polymeric material to be coated. The stent can be dipped into the polymeric material/bioactive agent blend thereby coating the blend onto the stent.
EXAMPLE 7
[0062] A stent as described in Example 5 can be further dipped into a polymeric material/bioactive agent blend of Example 6. The resulting stent will have a combined degradation time of at least 9 months and can elute an mTOR inhibitor from both coatings.
[0100] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0101] The terms "a," "an," "the" and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0102] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
[0103] Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
[0104] Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above-cited references and printed publications are individually incorporated herein by reference in their entirety.
[0105] In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.
Claims
1. A stent comprising:
(a) a magnesium based core structure, said core structure having a first degradation time;
(b) at least one polymeric material coated on at least a portion of said core structure, said polymeric material having an ability to slow said degradation time such that said polymeric material coated on at least a portion of said core has a second degradation time; and
(c) at least one bioactive agent associated with said at least one polymeric material.
2. The stent according to claim 1 wherein said stent is selected from the group consisting of woven stents, individual ring stents, sequential ring stents, closed cell stents, open cell stents, laser cut tube stents, ratchet stents, and modular stents.
3. The stent according to claim 1 wherein said magnesium based core structure comprises magnesium and magnesium alloys.
4. The stent according to claim 1 wherein said second degradation time is between 1 month and 12 months.
5. The stent according to claim 1 wherein said polymeric material comprises a top coat.
6. The stent according to claim 1 wherein said at least one polymeric material comprises polymers selected from the group consisting of polylactide, poylglycolide, polysaccharides, proteins, polyesters, polyhydroxyalkanoates, polyalkelene esters, polyamides, polycaprolactone, polyvinyl esters, polyamide esters, polyvinyl alcohols, modified derivatives of caprolactone polymers, polytrimethylene carbonate, polyacrylates, polyethylene glycol, hydrogels, photo-curable hydrogels, terminal diols, and combinations thereof.
7. The stent according to claim 1 wherein said at least one bioactive agent is selected from the group consisting of anti-proliferatives, mTOR inhibitors, estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, leptomycin B, peroxisome proliferator-activated receptor gamma ligands (PPARγ), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, proteasome inhibitors, antibiotics, anti-inflammatories, anti-sense nucleotides, transforming nucleic acids, sirolimus (rapamycin), tacrolimus (FK506), everolimus (certican), temsirolimus (CCI-779) and zotarolimus (ABT-578).
8. The stent according to claim 1 wherein said at least one bioactive agent is coated on said polymeric material.
9. The stent according to claim 1 wherein said at least one bioactive agent is dispersed within said polymer material.
10. A method of prolonging the life of an implantable magnesium based medical device comprising:
(a) providing a magnesium based core structure comprising a first degradation time;
(b) choosing at least one appropriate bioabsorbable polymeric material;
(c) coating at least a portion of said core structure with said polymeric material forming a coated medical device, thereby retarding the degradation of said core structure; and
(d) providing a medical device having a second degradation time.
11. The method according to claim 10 wherein said magnesium based core structure comprises magnesium and magnesium alloys.
12. The method according to claim 10 wherein said first degradation time is less than 1 month.
13. The method according to claim 11 wherein said second degradation time is between 1 month and 12 months.
14. The method according to claim 11 wherein said at least one polymeric material is bioabsorbable and comprises polymers selected from the group consisting of polylactide, poylglycolide, polysaccharides, proteins, polyesters, polyhydroxyalkanoates, polyalkelene esters, polyamides, polycaprolactone, polyvinyl esters, polyamide esters, polyvinyl alcohols, modified derivatives of caprolactone polymers, polytrimethylene carbonate, polyacrylates, polyethylene glycol, hydrogels, photo-curable hydrogels, terminal diols, and combinations thereof.
15. The method according to claim 11 wherein said at least one polymeric material is a top coat.
16. The method according to claim 11 wherein said bioactive agent is selected from the group consisting of anti-proliferatives, mTOR inhibitors, estrogens, chaperone inhibitors, protease inhibitors, protein-tyrosine kinase inhibitors, leptomycin B, peroxisome proliferator-activated receptor gamma ligands (PPARγ), hypothemycin, nitric oxide, bisphosphonates, epidermal growth factor inhibitors, antibodies, proteasome inhibitors, antibiotics, antiinflammatories, anti- sense nucleotides, transforming nucleic acids, sirolimus (rapamycin), tacrolimus (FK506), everolimus (certican), temsirolimus (CCI-779) and zotarolimus (ABT-578).
17. The method according to claim 11 wherein said bioactive agent is coated on said at least one polymeric material.
18. The method according to claim 11 wherein said bioactive agent is dispersed within said at least one polymer material.
19. The method according to claim 11 wherein said implantable medical device is selected from the group consisting of woven stents, individual ring stents, sequential ring stents, closed cell stents, open cell stents, laser cut tube stents, ratchet stents, and modular stents.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011500850A JP2011517415A (en) | 2008-03-20 | 2009-03-03 | Magnesium stent with controlled degradation |
CN2009801147388A CN102014978A (en) | 2008-03-20 | 2009-03-03 | Controlled degradation of magnesium stents |
EP09722892A EP2268333A2 (en) | 2008-03-20 | 2009-03-03 | Controlled degradation of magnesium stents |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/052,538 | 2008-03-20 | ||
US12/052,538 US20090240323A1 (en) | 2008-03-20 | 2008-03-20 | Controlled Degradation of Magnesium Stents |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2009117241A2 true WO2009117241A2 (en) | 2009-09-24 |
WO2009117241A3 WO2009117241A3 (en) | 2010-07-15 |
Family
ID=40637972
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2009/035809 WO2009117241A2 (en) | 2008-03-20 | 2009-03-03 | Controlled degradation of magnesium stents |
Country Status (5)
Country | Link |
---|---|
US (1) | US20090240323A1 (en) |
EP (1) | EP2268333A2 (en) |
JP (1) | JP2011517415A (en) |
CN (1) | CN102014978A (en) |
WO (1) | WO2009117241A2 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013543761A (en) * | 2010-11-09 | 2013-12-09 | トランスルミナル テクノロジーズ リミテッド ライアビリティー カンパニー | Specially designed magnesium-aluminum alloy and its use in medicine in hemodynamic environment |
WO2017041555A1 (en) * | 2015-09-07 | 2017-03-16 | 先健科技(深圳)有限公司 | Absorbable occluder |
US9901663B2 (en) | 2013-05-06 | 2018-02-27 | Abbott Cardiovascular Systems Inc. | Hollow stent filled with a therapeutic agent formulation |
EP3381415A4 (en) * | 2015-11-26 | 2019-07-24 | JAPAN Medical Device Technology Co., Ltd. | Bioabsorbable stent |
Families Citing this family (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003002243A2 (en) | 2001-06-27 | 2003-01-09 | Remon Medical Technologies Ltd. | Method and device for electrochemical formation of therapeutic species in vivo |
US8840660B2 (en) | 2006-01-05 | 2014-09-23 | Boston Scientific Scimed, Inc. | Bioerodible endoprostheses and methods of making the same |
US8089029B2 (en) | 2006-02-01 | 2012-01-03 | Boston Scientific Scimed, Inc. | Bioabsorbable metal medical device and method of manufacture |
US8048150B2 (en) | 2006-04-12 | 2011-11-01 | Boston Scientific Scimed, Inc. | Endoprosthesis having a fiber meshwork disposed thereon |
WO2008017028A2 (en) | 2006-08-02 | 2008-02-07 | Boston Scientific Scimed, Inc. | Endoprosthesis with three-dimensional disintegration control |
JP2010503491A (en) | 2006-09-15 | 2010-02-04 | ボストン サイエンティフィック リミテッド | Bioerodible endoprosthesis with biologically stable inorganic layers |
US8052744B2 (en) | 2006-09-15 | 2011-11-08 | Boston Scientific Scimed, Inc. | Medical devices and methods of making the same |
WO2008034031A2 (en) | 2006-09-15 | 2008-03-20 | Boston Scientific Limited | Bioerodible endoprostheses and methods of making the same |
US8057534B2 (en) | 2006-09-15 | 2011-11-15 | Boston Scientific Scimed, Inc. | Bioerodible endoprostheses and methods of making the same |
WO2008036548A2 (en) | 2006-09-18 | 2008-03-27 | Boston Scientific Limited | Endoprostheses |
ES2356274T3 (en) | 2006-12-28 | 2011-04-06 | Boston Scientific Limited | BIODEGRADABLE ENDOPROTESIS AND MANUFACTURING PROCEDURES OF THE SAME. |
US8052745B2 (en) | 2007-09-13 | 2011-11-08 | Boston Scientific Scimed, Inc. | Endoprosthesis |
US8118857B2 (en) * | 2007-11-29 | 2012-02-21 | Boston Scientific Corporation | Medical articles that stimulate endothelial cell migration |
US7998192B2 (en) | 2008-05-09 | 2011-08-16 | Boston Scientific Scimed, Inc. | Endoprostheses |
US20090287301A1 (en) * | 2008-05-16 | 2009-11-19 | Boston Scientific, Scimed Inc. | Coating for medical implants |
US8236046B2 (en) | 2008-06-10 | 2012-08-07 | Boston Scientific Scimed, Inc. | Bioerodible endoprosthesis |
US7985252B2 (en) | 2008-07-30 | 2011-07-26 | Boston Scientific Scimed, Inc. | Bioerodible endoprosthesis |
US8382824B2 (en) | 2008-10-03 | 2013-02-26 | Boston Scientific Scimed, Inc. | Medical implant having NANO-crystal grains with barrier layers of metal nitrides or fluorides |
EP2403546A2 (en) | 2009-03-02 | 2012-01-11 | Boston Scientific Scimed, Inc. | Self-buffering medical implants |
US8435281B2 (en) | 2009-04-10 | 2013-05-07 | Boston Scientific Scimed, Inc. | Bioerodible, implantable medical devices incorporating supersaturated magnesium alloys |
WO2011119573A1 (en) | 2010-03-23 | 2011-09-29 | Boston Scientific Scimed, Inc. | Surface treated bioerodible metal endoprostheses |
EP2585125B1 (en) | 2010-06-25 | 2014-11-19 | Fort Wayne Metals Research Products Corporation | Biodegradable composite wire for medical devices |
JP6017424B2 (en) | 2010-09-08 | 2016-11-02 | シンセス ゲゼルシャフト ミット ベシュレンクテル ハフツングSynthes Gmbh | Fixing device with magnesium core |
CN102327862B (en) * | 2011-07-12 | 2014-03-12 | 成都西南交大科技园管理有限责任公司 | Polymer composite coating technology capable of reducing corrosion rates of magnesium-based material and magnesium-based material device |
US20130060348A1 (en) | 2011-09-01 | 2013-03-07 | Tyco Healthcare Group Lp | Hydrogel Coated Magnesium Medical Implants |
GB201116879D0 (en) * | 2011-09-30 | 2011-11-16 | Magnus Stent Ic | Endoprosthesis |
CN102908216A (en) * | 2012-10-30 | 2013-02-06 | 东南大学 | Biodegradable medical human body cavity channel inner bracket and preparation method thereof |
CN103877624B (en) | 2012-12-21 | 2016-05-25 | 上海微创医疗器械(集团)有限公司 | A kind of degradable polyester support and preparation method thereof |
EP2767294B1 (en) | 2013-02-13 | 2018-03-21 | Biotronik AG | Biocorrodible implant with anti-corrosion coating |
EP2767295B1 (en) | 2013-02-13 | 2015-11-04 | Biotronik AG | Biocorrodible implant with anti-corrosion coating |
DE102013214636A1 (en) | 2013-07-26 | 2015-01-29 | Heraeus Medical Gmbh | Bioresorbable material composites containing magnesium and magnesium alloys as well as implants from these composites |
CN106456847A (en) | 2014-07-22 | 2017-02-22 | 百多力股份公司 | Biodegradable metal stent and methods |
JP2016163619A (en) * | 2015-03-06 | 2016-09-08 | 株式会社日本ステントテクノロジー | Magnesium degradation rate control using anticorrosion effect |
WO2016163339A1 (en) * | 2015-04-07 | 2016-10-13 | 二プロ株式会社 | Stent |
JP6558569B2 (en) * | 2015-05-21 | 2019-08-14 | ニプロ株式会社 | Stent |
JP2019516468A (en) * | 2016-05-25 | 2019-06-20 | キュースリー メディカル デヴァイシズ リミテッドQ3 Medical Devices Limited | Biodegradable support device |
CN106178139A (en) * | 2016-07-05 | 2016-12-07 | 苏州脉悦医疗科技有限公司 | A kind of support and preparation method thereof |
US20190240374A1 (en) * | 2016-10-21 | 2019-08-08 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Degradable bulk metallic magnesium/polymer composite barrier membranes for dental, craniomaxillofacial and orthopedic applications and manufacturing methods |
CN106798952B (en) * | 2017-02-13 | 2019-12-10 | 先健科技(深圳)有限公司 | absorbable iron-based internal fracture fixation material |
US11191655B2 (en) * | 2018-11-04 | 2021-12-07 | Biosert Ltd. | Expanding stent |
CA3126019A1 (en) | 2019-01-18 | 2020-07-23 | W. L. Gore & Associates, Inc. | Bioabsorbable medical devices |
CA3125987A1 (en) * | 2019-01-18 | 2020-07-23 | W. L. Gore & Associates, Inc. | Bioabsorbable filament medical devices |
KR102168655B1 (en) | 2019-11-06 | 2020-10-21 | 한국섬유개발연구원 | Manufacturing method of composite sheath-core filament using biodegradable dissimilar materials and composite sheath-core filament manufactured the same |
AU2021230640B2 (en) | 2020-03-03 | 2023-12-14 | Hejie Li | Methods for improving mechanical property and biological stability of magnesium alloy and for manufacturing material and applications |
CN112472879A (en) * | 2020-12-21 | 2021-03-12 | 上海康德莱医疗器械股份有限公司 | Magnesium alloy stent and preparation method thereof |
CN114452448A (en) * | 2022-02-18 | 2022-05-10 | 常熟致圆微管技术有限公司 | Preparation method of biodegradable medical metal magnesium stent |
CN115531606B (en) * | 2022-09-30 | 2024-03-26 | 珠海奥华复维医疗技术有限公司 | Gradient degradation reticular implant, preparation method and application thereof |
CN118059321A (en) * | 2024-02-20 | 2024-05-24 | 深圳库珀医疗股份有限公司 | Surface-degradable drug-loaded ureteral stent and preparation method thereof |
Family Cites Families (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5362718A (en) * | 1994-04-18 | 1994-11-08 | American Home Products Corporation | Rapamycin hydroxyesters |
US10028851B2 (en) * | 1997-04-15 | 2018-07-24 | Advanced Cardiovascular Systems, Inc. | Coatings for controlling erosion of a substrate of an implantable medical device |
US6015815A (en) * | 1997-09-26 | 2000-01-18 | Abbott Laboratories | Tetrazole-containing rapamycin analogs with shortened half-lives |
US6338739B1 (en) * | 1999-12-22 | 2002-01-15 | Ethicon, Inc. | Biodegradable stent |
US6730873B2 (en) * | 2002-07-05 | 2004-05-04 | Eric Wolfe | Oxy-carbon arc cutting electrode |
US20050163821A1 (en) * | 2002-08-02 | 2005-07-28 | Hsing-Wen Sung | Drug-eluting Biodegradable Stent and Delivery Means |
DE10237572A1 (en) * | 2002-08-13 | 2004-02-26 | Biotronik Meß- und Therapiegeräte GmbH & Co. Ingenieurbüro Berlin | Stent with a polymer coating |
US20060121080A1 (en) * | 2002-11-13 | 2006-06-08 | Lye Whye K | Medical devices having nanoporous layers and methods for making the same |
CA2527975C (en) * | 2003-06-13 | 2011-08-09 | Mnemoscience Gmbh | Biodegradable stents comprising a shape memory polymeric material |
US20060052825A1 (en) * | 2003-06-16 | 2006-03-09 | Ransick Mark H | Surgical implant alloy |
US7758892B1 (en) * | 2004-05-20 | 2010-07-20 | Boston Scientific Scimed, Inc. | Medical devices having multiple layers |
US20060177480A1 (en) * | 2005-02-10 | 2006-08-10 | Hsing-Wen Sung | Drug-eluting biodegradable stent |
US20060198869A1 (en) * | 2005-03-03 | 2006-09-07 | Icon Medical Corp. | Bioabsorable medical devices |
JP5312018B2 (en) * | 2005-04-05 | 2013-10-09 | エリクシアー メディカル コーポレイション | Degradable implantable medical device |
US20070038290A1 (en) * | 2005-08-15 | 2007-02-15 | Bin Huang | Fiber reinforced composite stents |
US20070050009A1 (en) * | 2005-08-30 | 2007-03-01 | Aiden Flanagan | Bioabsorbable stent |
US20070135908A1 (en) * | 2005-12-08 | 2007-06-14 | Zhao Jonathon Z | Absorbable stent comprising coating for controlling degradation and maintaining pH neutrality |
US20070191931A1 (en) * | 2006-02-16 | 2007-08-16 | Jan Weber | Bioerodible endoprostheses and methods of making the same |
US20070224244A1 (en) * | 2006-03-22 | 2007-09-27 | Jan Weber | Corrosion resistant coatings for biodegradable metallic implants |
WO2007136969A2 (en) * | 2006-05-16 | 2007-11-29 | Medtronic Vascular, Inc. | Bioabsorbable magnesium-reinforced polymer stents |
US7951194B2 (en) * | 2006-05-26 | 2011-05-31 | Abbott Cardiovascular Sysetms Inc. | Bioabsorbable stent with radiopaque coating |
US8703167B2 (en) * | 2006-06-05 | 2014-04-22 | Advanced Cardiovascular Systems, Inc. | Coatings for implantable medical devices for controlled release of a hydrophilic drug and a hydrophobic drug |
DE102006029247A1 (en) * | 2006-06-26 | 2007-12-27 | Biotronik Vi Patent Ag | Implant with a coating comprises one or more components such as cholesterol or cholesterol ester |
DE102006038236A1 (en) * | 2006-08-07 | 2008-02-14 | Biotronik Vi Patent Ag | Biodegradable stent with an active coating |
DE102006038231A1 (en) * | 2006-08-07 | 2008-02-14 | Biotronik Vi Patent Ag | Implant of a biocorrodible metallic material with a coating of an organosilicon compound |
DE102006038235A1 (en) * | 2006-08-07 | 2008-02-14 | Biotronik Vi Patent Ag | Improving the stability of biodegradable metallic stents, methods and use |
DE102006038241A1 (en) * | 2006-08-07 | 2008-02-14 | Biotronik Vi Patent Ag | Stent with a genisteinhaltigen coating or Kavitätenfüllung |
JP2010503486A (en) * | 2006-09-18 | 2010-02-04 | ボストン サイエンティフィック リミテッド | Endoprosthesis |
US8974814B2 (en) * | 2007-11-12 | 2015-03-10 | California Institute Of Technology | Layered drug delivery polymer monofilament fibers |
-
2008
- 2008-03-20 US US12/052,538 patent/US20090240323A1/en not_active Abandoned
-
2009
- 2009-03-03 CN CN2009801147388A patent/CN102014978A/en active Pending
- 2009-03-03 JP JP2011500850A patent/JP2011517415A/en active Pending
- 2009-03-03 EP EP09722892A patent/EP2268333A2/en not_active Withdrawn
- 2009-03-03 WO PCT/US2009/035809 patent/WO2009117241A2/en active Application Filing
Non-Patent Citations (1)
Title |
---|
None |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013543761A (en) * | 2010-11-09 | 2013-12-09 | トランスルミナル テクノロジーズ リミテッド ライアビリティー カンパニー | Specially designed magnesium-aluminum alloy and its use in medicine in hemodynamic environment |
US9155530B2 (en) | 2010-11-09 | 2015-10-13 | Transluminal Technologies, Llc | Specially designed magnesium-aluminum alloys and medical uses thereof in a hemodynamic environment |
US9901663B2 (en) | 2013-05-06 | 2018-02-27 | Abbott Cardiovascular Systems Inc. | Hollow stent filled with a therapeutic agent formulation |
WO2017041555A1 (en) * | 2015-09-07 | 2017-03-16 | 先健科技(深圳)有限公司 | Absorbable occluder |
EP3381415A4 (en) * | 2015-11-26 | 2019-07-24 | JAPAN Medical Device Technology Co., Ltd. | Bioabsorbable stent |
AU2016361380B2 (en) * | 2015-11-26 | 2021-04-08 | Japan Medical Device Technology Co., Ltd. | Bioabsorbable stent |
US11207448B2 (en) | 2015-11-26 | 2021-12-28 | Japan Medical Device Technology Co., Ltd. | Bioabsorbable stent |
Also Published As
Publication number | Publication date |
---|---|
EP2268333A2 (en) | 2011-01-05 |
JP2011517415A (en) | 2011-06-09 |
WO2009117241A3 (en) | 2010-07-15 |
CN102014978A (en) | 2011-04-13 |
US20090240323A1 (en) | 2009-09-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20090240323A1 (en) | Controlled Degradation of Magnesium Stents | |
US20070270940A1 (en) | Bioabsorbable Magnesium-Reinforced Polymer Stents | |
US7442721B2 (en) | Durable biocompatible controlled drug release polymeric coatings for medical devices | |
US9254350B2 (en) | Implantable medical devices having bioabsorbable primer polymer coatings | |
Commandeur et al. | Polymers, drug release, and drug‐eluting stents | |
Mani et al. | Coronary stents: a materials perspective | |
US8137687B2 (en) | 4-aza-caprolactone-based polymeric compositions useful for the manufacture of biodegradable medical devices and as medical device coatings | |
EP2268329B1 (en) | Implantable medical device coatings with improved mechanical stability | |
EP2265298A2 (en) | Biodegradable carbon diazeniumdiolate based nitric oxide donating polymers | |
US9056153B2 (en) | Biocompatible polymers for coating or fabricating implantable medical devices | |
Lockwood et al. | In vitro and in vivo characterization of novel biodegradable polymers for application as drug-eluting stent coatings | |
WO2002024249A2 (en) | Method for immobilizing poly(hema) on stents | |
CN112368030A (en) | Improvements in polymer layers on degradable devices | |
EP2285429B1 (en) | Reducing bioabsorption time of polymer coated implantable medical devices using polymer blends | |
US20120239140A1 (en) | Medical product comprising an active coating | |
Wu et al. | Coronary arterial drug-eluting stent: from structure to clinical | |
JP2015154921A (en) | drug sustained-release stent | |
JP7531480B2 (en) | Improving polymer layers on degradable devices | |
Guildford et al. | Cardiovascular stents | |
Schmitz et al. | Drug-eluting stent technologies for vascular regeneration | |
WO2010046637A2 (en) | Coating ii | |
Paul et al. | Recent advancements in pharmacological stent therapy using polymeric materials: Opportunities and challenges | |
Uurto | Preclinical Evaluation of New Drug-Eluting Biodegradable Poly-D/L-lactic Acid Vascular Stent | |
LAKSHMANA PENDYALA et al. | Passive and Active Polymer Coatings for Intracoronary Stents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200980114738.8 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09722892 Country of ref document: EP Kind code of ref document: A2 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011500850 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009722892 Country of ref document: EP |